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Captur, Gabriella, Eloisa Arbustini, Petros Syrris, Dina Radenkovic, Ben O'Brien, William J. Mckenna, and James C. Moon. "Lamin mutation location predicts cardiac phenotype severity: combined analysis of the published literature." Open Heart 5, no. 2 (October 2018): e000915. http://dx.doi.org/10.1136/openhrt-2018-000915.
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ObjectiveTwo LMNA genotype–phenotype cardiac correlations are reported: first, that cardiac involvement in multisystem laminopathies prevails with mutations upstream of the nuclear localisation signal (NLS); second, that worse outcomes occur with non-missense (compared with missense) mutations. We tested whether LMNA mutation DNA location and mutation subtype can predict phenotype severity in patients with lamin heart disease.MethodsWe used a semantic workflow platform and manual electronic literature search to identify published LMNA mutations with cardiac-predominant phenotype. Hierarchical cluster analysis (HCA) assembled lamin heart disease into classes based on phenotype severity. 176 reported causative mutations were classified and any relationships to mutation location/subtype assessed by contingency analysis.ResultsMore adverse phenotype was associated with mutation location upstream of the NLS (p=0.014, OR 2.38, 95% CI 1.19 to 4.80) but not with non-missense mutations (p=0.337, OR 1.36, 95% CI 0.72 to 2.57), although an association with non-missense mutations was identified in a subcluster with malignant ventricular arrhythmia (p=0.005, OR 2.64, 95% CI 0.76 to 9.21). HCA limited to the 65 mutations described on ClinVar as pathogenic/likely pathogenic showed similar findings (upstream of NLS, p=0.030, OR 4.78, 95% CI 1.28 to 17.83; non-missense, p=0.121, OR 2.64, 95% CI 0.76 to 9.21) as did analysis limited to pathogenic/likely pathogenic variants according to the American College of Medical Genetics and Genomics standards.ConclusionCardiac patients with an LMNA mutation located upstream versus downstream of the NLS have a more adverse cardiac phenotype, and some missense mutations can be as harmful as non-missense ones.
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Caspi, Michal, Frédéric M. Coquelle, Cynthia Koifman, Talia Levy, Hiroyuki Arai, Junken Aoki, Jan R. De Mey, and Orly Reiner. "LIS1 Missense Mutations." Journal of Biological Chemistry 278, no. 40 (July 28, 2003): 38740–48. http://dx.doi.org/10.1074/jbc.m301147200.
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Prophet, Malshundria, Kun Xiao, Theodore Stewart Gourdin, Rebecca J. Nagy, Lesli Ann Kiedrowski, Elisa Ledet, Guru Sonpavde, A. Oliver Sartor, and Michael B. Lilly. "Detection of actionable BRAF missense mutations by ctDNA-based genomic analysis in prostate cancer." Journal of Clinical Oncology 36, no. 6_suppl (February 20, 2018): 306. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.306.
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306 Background: Activating BRAF fusion proteins are rare in prostate cancer (PCa) patients. Driver missense BRAF mutations have not been reported in detail in this population. Methods: We examined ctDNA-derived genomic profiles (Guardant 360) from 2,721 unique PCa patients, to identify BRAF genomic anomalies (SNVs, amplification). The ctDNA results were compared with PCa tissue-based genomics from the TCGA database (1,851 unique patients). Results: BRAF missense mutations were found in 76 ctDNA patients (2.8%) and were from all known mutation classes (I, II, III) as well as variants of unknown significance (VUSs). Only 4 patients had the V600E mutation. Multiple examples of known, autonomously active, non-canonical mutations were found (27), including K601E (12), G469A (5), D594G (2), and G466E (2). There were 45 VUSs. Mutations were primarily clonal but subclonal mutations were also found. In addition BRAF was commonly amplified, usually in the presence of multiple other amplified genes. BRAF missense mutations were more common with ctDNA than TCGA (2.8% vs 1.4%). Neither dataset identified frequent V600E mutations (ctDNA: 4/2,721; TCGA 1/1,851). However patients with the same non-canonical BRAF mutations were found in each dataset (K601E, G469A, G466E, D594G). Each dataset contained unique mutations found in only one patient. BRAF mutations potentially treatable with BRAF or MEK inhibitors (class I, II) were about half of all mutations (ctDNA 40.8%; TCGA 50%). We treated a PCa patient with a clonal BRAF(G469A) mutation with targeted therapy. The patient was resistant to multiple lines of hormonal and cytotoxic therapy. Trametinib produced a clinical and RECIST response. Conclusions: ctDNA-based genomic analysis identified multiple BRAF amplifications and missense SNVs in PCa patients. SNVs are largely non-canonical, but include known activating mutations that could act as drivers. The analysis also identified more BRAF missense mutations than did tissue genomic profiling, but the mutational landscape, overall frequency of mutations was similar with either method. ctDNA-based genomic profiling can identify actionable BRAF driver mutations that may respond to MEK and BRAF inhibitors.
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Zhang, Edward D., Meixia Zhang, Gen Li, Charlotte L. Zhang, Zhihuan Li, Guangxi Zang, Zhiguang Su, et al. "Mutation spectrum in GNAQ and GNA11 in Chinese uveal melanoma." Precision Clinical Medicine 2, no. 4 (November 13, 2019): 213–20. http://dx.doi.org/10.1093/pcmedi/pbz021.
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Abstract Uveal melanoma is the most common intraocular cancer in the adult eye. R183 and Q209 were found to be mutational hotspots in exon 4 and exon 5 of GNAQ and GNA11 in Caucasians. However, only a few studies have reported somatic mutations in GNAQ or GNA11 in uveal melanoma in Chinese. We extracted somatic DNA from paraffin-embedded biopsies of 63 Chinese uveal melanoma samples and sequenced the entire coding regions of exons 4 and 5 in GNAQ and GNA11. The results showed that 33% of Chinese uveal melanoma samples carried Q209 mutations while none had R183 mutation in GNAQ or GNA11. In addition, seven novel missense somatic mutations in GNAQ (Y192C, F194L, P170S, D236N, L232F, V230A, and M227I) and four novel missense somatic mutations in GNA11 (R166C, I200T, S225F, and V206M) were found in our study. The high mutation frequency of Q209 and the novel missense mutations detected in this study suggest that GNAQ and GNA11 are common targets for somatic mutations in Chinese uveal melanoma.
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Kim, Soo-Hyun, Soo Young Choi, Sung-Eun Lee, Yun Jeong Oh, Jin-Eok Park, Hae Lyun Yoo, Hye-Rim Jeon, Eun-Jung Jang, and Dong-Wook Kim. "Kinetics Of Low-Level Mutant Clones Detected By Subcloning and Sequencing In Tyrosine Kinase Inhibitor Resistant CML." Blood 122, no. 21 (November 15, 2013): 2720. http://dx.doi.org/10.1182/blood.v122.21.2720.2720.
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Abstract Background BCR-ABL1 kinase domain (KD) point mutation causes resistance to tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML) patients through impaired binding of TKI to the target site. Recent studies have reported that multiple mutations detected in 2-9% of patients with imatinib (IM)-resistant CML were associated with poor response rate and survival outcomes. However, biological characteristics and dynamics of multiple low-level mutations are still not assessed with a quantitative serial follow-up data in the same populations. Aims The aim of this study was to investigate biological characteristics and dynamics of low-level mutations in the serial samples from the patients carrying multiple mutations using subcloning and sequencing. Methods Since 2002, 414 CML patients were screened for mutation analysis due to sign of resistance to TKIs including imatinib (IM), nilotinib (NIL), dasatinib (DAS), bosutinib (BOS), radotinib (RAD) or ponatinib (PON) at Seoul St Mary’s Hospital using direct sequencing and allele specific oligonucleotide-polymerase chain reaction (ASO-PCR). Among them, 31 patients carried ≥ 2 BCR-ABL1 kinase domain mutations. We analyzed 137 samples from these 31 patients using subcloning and sequencing (in total, 2737 colonies were sequenced). By cloning and sequencing, two or more missense mutations present in the same clone were defined as compound mutation and co-existence of single missense mutations in the separated clones was defined as polyclonal mutation. Co-existence of single missense mutation and compound mutation harboring two or more missense mutations in the same clone was defined as mixed mutation. Missense mutations detected by direct sequencing are defined as predominant mutations. Missense mutations detected by cloning and sequencing but not by direct sequencing are defined as low-level mutations. Results In a total of 2737 colonies from 137 samples, 1596 (58%) colonies harbored ≥ 2 missense mutations with a median 2 (range, 2 – 7) mutations, and 905 (33%) colonies with a single mutation and 236 (9%) colonies with wild type were observed. In 2737 colonies, 692 different low-level mutations were detected by cloning and sequencing but not by direct sequencing. Among them, M244V, G250E, Y253H, E279K, T315I, F317L, M351T, E355A, F359I, and F359V were detected by direct sequencing in the followed-up samples, and the others remain undetectable by direct sequencing. To address whether these low-level mutations were distinct in the patients with TKI resistance, we applied the cloning and sequencing to samples from 3 healthy controls and 3 patients with optimal response to IM. 38 different mutations were detected healthy controls. 52 different mutations were detected in optimal responders. S349P, N374S, E450G, and S485P were detected in both healthy controls and optimal responders. All mutations detected in optimal responders except 3 missense mutations (V335A, F382V, and A395S) were detected as low-level mutations in the 31 patients’ cohort with TKI resistance. Of 38 different mutations detected in healthy control, 31 mutations except 7 missense mutations (Y264H, M343R, A350V, E373G, G298R, E462K, and T495K) were also detected as low-level mutations in the 31 patients’ cohort. Conclusions We showed basic characteristics and dynamics of low-level mutations by subcloning and sequencing. Some of the low-level mutant clones harboring previously known (clinically common) TKI resistant mutations changes to the predominant in the followed-up samples. Except them, most low-level mutant clones were not detected repeatly and did not increase gradually in the serial samples, implying that they may not have clinical significance. Disclosures: No relevant conflicts of interest to declare.
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Boettcher, Steffen, Peter G. Miller, Rohan Sharma, Marie McConkey, Matthew Leventhal, Andrei V. Krivtsov, Andrew O. Giacomelli, et al. "A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies." Science 365, no. 6453 (August 8, 2019): 599–604. http://dx.doi.org/10.1126/science.aax3649.
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TP53, which encodes the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, are enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We used CRISPR-Cas9 to generate isogenic human leukemia cell lines of the most common TP53 missense mutations. Functional, DNA-binding, and transcriptional analyses revealed loss of function but no GOF effects. Comprehensive mutational scanning of p53 single–amino acid variants demonstrated that missense variants in the DNA-binding domain exert a dominant-negative effect (DNE). In mice, the DNE of p53 missense variants confers a selective advantage to hematopoietic cells on DNA damage. Analysis of clinical outcomes in patients with acute myeloid leukemia showed no evidence of GOF for TP53 missense mutations. Thus, a DNE is the primary unit of selection for TP53 missense mutations in myeloid malignancies.
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Shih, Lee-Yung, Der-Cherng Liang, Chein-Fuang Huang, Ming-Chung Kuo, Tung-Liang Lin, Jen-Fen Fu, Yu-Shu Shih, et al. "Different Patterns of AML1 Mutations between De Novo Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia." Blood 110, no. 11 (November 16, 2007): 2442. http://dx.doi.org/10.1182/blood.v110.11.2442.2442.
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Abstract Background: Transcription factor AML1/RUNX1 is essential for normal hematopoiesis. AML1 mutations have been described in radiation-associated and therapy-related myelodysplastic syndrome (MDS) and have rarely been reported in patients with chronic myelomonocytic leukemia (CMML). Aims: We sought (1) to define the frequencies of AML1 mutations in de novo MDS and CMML, and (2) to compare the difference in mutation patterns between the two disorders. Methods: AML1 mutations were examined on bone marrow samples obtained at initial diagnosis from 107 patients with de novo MDS (12 RCMD, 45 RAEB1 and 50 RAEB2) and 79 patients with CMML (53 CMML1 and 26 CMML2). Mutational analysis was performed by direct sequencing of all RT-PCR products amplified with 3 overlapping primer pairs which cover the entire coding sequences of AML1b gene from exon 1 through exon 8. Samples with abnormal sequencing results were subjected to repeated PCR and sequencing using genomic DNA with alternative primers. Results: Seventeen of 107 patients with MDS (15.9%) had 20 AML1 mutations; 8 mutations were located in Runt homology domain (RHD) (exons 3–5) and 12 mutations were located in the non-RHD region (exons 6–8). The 20 AML1 mutations included 9 missense mutations, 5 nonsense mutations, 2 frameshift mutations, and 4 silent mutations. One patient has two missense mutations at RHD and another two had one missense mutation with one silent mutation. Thirty-one AML1 mutations were detected in 29 of 79 CMML patients (36.7%); 20 patients had 22 mutations located in the N-terminal part and the remaining 9 patients had one single mutation located in the C-terminal region. The patterns of the 31 mutations consisted of 8 missense mutations, 7 nonsense mutations, 15 frameshift mutations and 1 silent mutation. One CMML patient had two missense mutations in RHD and another patient had two frameshift mutations in RHD. Cloning analysis showed that the two mutations were on different alleles in both patients. The frequency of AML1 mutations was significantly higher in patients with CMML than in MDS (P=0.002). Mutations in N-terminal region occurred more frequently in CMML than in MDS (22/30 vs. 8/20, P=0.042). CMML patients had a higher frequency of frameshift mutations as compared with MDS patients (P=0.006). Except for a significantly lower platelet count in CMML patients with AML1 mutations, there were no differences in age, sex, blood counts, percentages of blasts in bone marrow or peripheral blood, subtypes of MDS or CMML, cytogenetic risk groups, time to AML transformation or overall survival between AML1(+) and AML1(−) in MDS and between AML1(+) and AML1(−) CMML patients. Conclusion: Our results showed that AML1 mutations occurred frequently in both de novo MDS and CMML but with different mutation patterns.
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Zabransky, Daniel J., Christopher L. Yankaskas, Rory L. Cochran, Hong Yuen Wong, Sarah Croessmann, David Chu, Shyam M. Kavuri, et al. "HER2 missense mutations have distinct effects on oncogenic signaling and migration." Proceedings of the National Academy of Sciences 112, no. 45 (October 27, 2015): E6205—E6214. http://dx.doi.org/10.1073/pnas.1516853112.
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Recurrent human epidermal growth factor receptor 2 (HER2) missense mutations have been reported in human cancers. These mutations occur primarily in the absence of HER2 gene amplification such that most HER2-mutant tumors are classified as “negative” by FISH or immunohistochemistry assays. It remains unclear whether nonamplified HER2 missense mutations are oncogenic and whether they are targets for HER2-directed therapies that are currently approved for the treatment of HER2 gene-amplified breast cancers. Here we functionally characterize HER2 kinase and extracellular domain mutations through gene editing of the endogenous loci in HER2 nonamplified human breast epithelial cells. In in vitro and in vivo assays, the majority of HER2 missense mutations do not impart detectable oncogenic changes. However, the HER2 V777L mutation increased biochemical pathway activation and, in the context of a PIK3CA mutation, enhanced migratory features in vitro. However, the V777L mutation did not alter in vivo tumorigenicity or sensitivity to HER2-directed therapies in proliferation assays. Our results suggest the oncogenicity and potential targeting of HER2 missense mutations should be considered in the context of cooperating genetic alterations and provide previously unidentified insights into functional analysis of HER2 mutations and strategies to target them.
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Zhang, Zhe, Maria A. Miteva, Lin Wang, and Emil Alexov. "Analyzing Effects of Naturally Occurring Missense Mutations." Computational and Mathematical Methods in Medicine 2012 (2012): 1–15. http://dx.doi.org/10.1155/2012/805827.
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Single-point mutation in genome, for example, single-nucleotide polymorphism (SNP) or rare genetic mutation, is the change of a single nucleotide for another in the genome sequence. Some of them will produce an amino acid substitution in the corresponding protein sequence (missense mutations); others will not. This paper focuses on genetic mutations resulting in a change in the amino acid sequence of the corresponding protein and how to assess their effects on protein wild-type characteristics. The existing methods and approaches for predicting the effects of mutation on protein stability, structure, and dynamics are outlined and discussed with respect to their underlying principles. Available resources, either as stand-alone applications or webservers, are pointed out as well. It is emphasized that understanding the molecular mechanisms behind these effects due to these missense mutations is of critical importance for detecting disease-causing mutations. The paper provides several examples of the application of 3D structure-based methods to model the effects of protein stability and protein-protein interactions caused by missense mutations as well.
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Vierimaa, O., T. M. L. Ebeling, S. Kytölä, R. Bloigu, E. Eloranta, J. Salmi, E. Korpi-Hyövälti, et al. "Multiple endocrine neoplasia type 1 in Northern Finland; clinical features and genotype–phenotype correlation." European Journal of Endocrinology 157, no. 3 (September 2007): 285–94. http://dx.doi.org/10.1530/eje-07-0195.
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Objective: The existence of genotype–phenotype correlation in multiple endocrine neoplasia type 1 (MEN1) is controversial. Two founder mutations of the MEN1 gene in Northern Finland gave us an opportunity to compare clinical features among heterozygotes of different mutations. Design and methods: Study cohort included 82 MEN1 heterozygotes who were tested for MEN1 during the years 1982–2001. Medical records were reviewed for manifestations of MEN1, other tumours and cause of death by the end of August 2003. Logistic regression analysis was used in evaluating the impact of age, gender and mutational status of affected heterozygotes on the likelihood of developing manifestations of MEN1. Results: Founder mutations 1466del12 and 1657insC were found in 39 and 29 individuals, and D418N, G156R and R527X mutations in 9, 3 and 2 individuals respectively. Except for pituitary adenoma and nonfunctional pancreatic tumour (NFPT), age was a risk factor for all the disease manifestations. For NFPT, frameshift/nonsense mutations (1657insC, R527X) gave an odds ratio (OR) of 3.26 (95% confidence intervals (CI), 1.27–8.33; P = 0.014) compared with in-frame/missense mutations (1466del12, D418N, G156R); including the founder mutation carriers (n = 68) only, the 1657insC mutation gave an OR of 3.56 (CI, 1.29–9.83; P = 0.015). For gastrinoma, in-frame/missense mutations predicted the risk with an OR of 6.77 (CI, 1.31–35.0; P = 0.022), and in the founder mutations group the 1466del12 mutation gave an OR of 15.09 (CI, 1.73–131.9, P = 0.014). Conclusions: In this study population, NFPT was more common in the frameshift/nonsense or 1657insC mutation carriers, whereas gastrinoma was more common in the in-frame/missense or 1466del12 mutation carriers.
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Pavlova, Anna, Thilo Albert, Michael Caspers, Johannes Oldenburg, and Rainer Schwaab. "Significance of F8 missense mutations with respect to inhibitor formation." Thrombosis and Haemostasis 109, no. 03 (2013): 464–70. http://dx.doi.org/10.1160/th12-07-0521.
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SummaryWe have identified 1,135 haemophilia A patients with missense mutations associated with mild (46%), moderate (22%), severe (16%), and mixed haemophilia phenotypes (11%). Altogether, we detected 374 different missense mutations of which 195 are not listed in the HAMSTeRS database. While missense mutations are strongly underrepresented within the factor VIII (FVIII) B-domain, they are evenly distributed throughout the entire F8 cDNA sequence. Only 36 (5%) of 720 patients with missense mutations and known inhibitor status showed an association with inhibitor formation. Inhibitor prevalence was four-fold higher for severe haemophilia compared to mild/moderate phenotypes. Mutations associated with inhibitor formation were especially clustered within the C1/C2 domain compared to the other domains (8.7% C1/C2 domain vs. 3.6% non-C1/C2-domain; p-value: 0.01). Three different missense mutations (T314A [T295A], S2010P [S1991P], R2169H [R2150H]) were associated twice with inhibitor formation. Importantly, we found that the risk of inhibitor formation in association with FVIII missense mutations is significant higher if the amino acid substitution belongs to another physicochemical class than the original residue (p-value 0.039). For this purpose distinct classes of substitutions were grouped in association with side chains properties: class I, small/hydrophobic; class II, neutral; class III, acidic; class IV, basic. Thus, although missense mutations were associated with an overall lower risk of inhibitor formation compared to other F8 gene mutation types, different missense mutations correlate with specific risks for inhibitor formation. These differences have to be identified in assigning risk profiles to aid in choice of preventative treatments designed to prevent inhibitor formation.
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Ivaskevicius, Vytautas, Arijit Biswas, Anne Thomas, Ramin Tehranchi, and Johannes Oldenburg. "Genetic Background in Patients with Severe Factor XIII A-Subunit Deficiency Treated with Recombinant FXIII." Blood 120, no. 21 (November 16, 2012): 1125. http://dx.doi.org/10.1182/blood.v120.21.1125.1125.
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Abstract Abstract 1125 Background and Objectives: Congenital Factor XIII (FXIII) deficiency is a rare, autosomal recessive bleeding disorder, with a significant majority of patients showing defects in the FXIII-A subunit. The disease is caused by a variety of F13A1 gene mutations resulting in a severe quantitative FXIII-A type I deficiency. Here, we report a wide spectrum of mutations identified in 41 severe Factor XIII-A deficiency patients (≥6 years of age, mean, 26.4; range, 7–60). Patients and Methods: A total of 41 patients were recruited in a multinational (23 centers, 11 countries), open-label, single-arm, phase 3, prophylaxis trial for the evaluation of the efficacy and safety of a novel recombinant FXIII (rFXIII). Eleven of the 41 patients (Israel [n=8], Switzerland [n=2] and Italy [n=1]) already had established genetic backgrounds and carried previously reported F13A1 mutations. Mutational screening in the remaining 30 patients who had unknown genetic status was done using direct sequencing on an ABI Prism 3130TL (Applied Biosystems, Weiterstadt, Germany). For two patients with splice-site mutations, cDNA analysis was done with RT-PCR (Quiagen One-step RT-PCR kit). The crystallographic model of the recombinant human cellular coagulation FXIIIA zymogen (EC: 2.3.2.13, resolution solved to 2.1Å) was downloaded from the Protein Data Bank (data file 1F13) for viewing, analysis and graphical rendering using YASARAver11.11.2. Classic molecular dynamic simulation approaches were used on the FXIII-A crystal structure to evaluate the effect of the novel missense mutations on protein structure. Results and Discussion: In total, 31 distinct mutations in 41 patients have been identified revealing 13 missense mutations, seven small deletions, six splice-site mutations, three nonsense mutations, one large deletion and one small insertion. Amongst this cohort of mutations, 16 mutations were novel. In one patient, a heterozygous missense mutation was detected in spite of severe deficiency symptoms shown by the patient. We assume that the other mutation could not be detected within the scope of our screening set up. The IVS5–1G>A (c.691–1G>A) splice-site mutation was the most commonly occurring (n=9 [21.9%]) mutation in this cohort. Two siblings carried a missense mutation in F13A1 gene (Ser295Arg) and in combination with a novel variant in F13B gene (Ser634Phe). This variant does not seem to significantly affect the B-subunit stability, since it is located in the terminal part of the molecule. Missense mutations are of special interest since they help to better understand the structure and function of FXIII A-subunit. The MD simulation of four novel missense mutations predicted a damaging effect on the protein structure for three of the missense mutations (Glu229Arg, Leu275Phe, and Arg703Trp) based on changes in bonding patterns, free energy calculations, change in local secondary structure etc. The Leu588Gln located on the surface of barrel 1 domain was not observed to cause a significant change in local structure, nevertheless, owing to its surface presentation it might influence the interaction with FXIII B-subunit. The analysis for the two novel splice-site mutations (IVS7+1G>A, IVS12+1G>A) did not show any aberrant mRNA product. Inhibitor development is the most undesirable side-effect of treatment with plasma-derived or rFXIII products. Overall, the incidence of inhibitors in patients with congenital FXIII deficiency is unknown, but is expected to be much lower compared with other coagulopathies, e.g. hemophilia A. In the present study, none of the patients treated with rFXIII (a mean treatment period of 322 days) developed FXIII neutralizing antibodies. Four patients developed transient low-titer anti-rFXIII antibodies that had no neutralizing activity. Interestingly, two patients (male and female) were siblings carrying the same common splice-site mutation in intron 5 (IVS5-1 G>A). The third patient was compound heterozygous for two missense mutations (Gln229Arg; Ser413Leu). The fourth patient was also found to be compound heterozygous for two missense mutations (Arg77His; Leu275Phe). Conclusion: To conclude, the identified mutations, including 16 novel mutations, are implicated in the causality of severe FXIII deficiency. However, none of these mutations were associated with the development of inhibitory antibodies in the context of treatment with rFXIII. Disclosures: Tehranchi: Novo Nordisk: Employment, Equity Ownership. Oldenburg:Biogen Idec, Swedish Orphan Biovitrum: Honoraria; Baxter, Bayer, Biotest, CSL Behring, Grifols, Inspiration, Novo Nordisk, Octapharma, Pfizer: Honoraria, Research Funding.
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Gábos, Gabriella, Dumitru Moldovan, Daniela Dobru, Enikő Mihály, Noémi Bara, Valentin Nădășan, Adina Hutanu, and Katalin Csép. "Mutational spectrum and genotype-phenotype relationships in a cohort of Romanian hereditary angioedema patients caused by C1 inhibitor deficiency." Revista Romana de Medicina de Laborator 27, no. 3 (July 1, 2019): 255–67. http://dx.doi.org/10.2478/rrlm-2019-0029.
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Abstract Background: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) caused by SERPING1 mutations is a rare monogenic disorder characterized by a high frequency of de novo mutations, allelic heterogeneity and populational differences. Geno- and phenotype correlation data are limited. Addressing the pathogenic complexity, we proposed to analyze the clinical and genetic characteristics in a set of Romanian patients. Material and Methods: 49 patients from 22 unrelated families with C1-INH-HAE were investigated, by calculating clinical severity score (CSS), C1-INH and C4 level assessment by nephelometric assays, C1-INH function study by functional enzyme-linked immunosorbent assay, and mutation analysis by sequencing and MLPA. Clinical manifestations by missense vs other mutation mechanisms were compared. Results: The mean age at diagnosis and onset was 28.8±14.7 and 15.1±15.2 years, while the diagnostic delay 13.1±10.1 years. CSS ranged from 2 to 9, with a mean of 5.4±1.8. The frequency of missense and nonsense mutations, splice defects, frameshift mutations and large gene rearrangements was 61.22, 6.12, 22.4, 6.12 and 4.08%; in the regulatory sequence no mutation was described. In type II, only missense mutations were noted. Lower levels of C1-INH characterized index cases caused by mechanisms other than missense mutation, with more severe consequences on protein synthesis (p=0.017). 53% of the cases were identified by familial screening. Conclusion: A later onset of disease manifestations and a higher frequency of missense mutations characterize HAE in Romanian patients with SERPING1 mutation. Genetic analysis improves the management of affected families, and may inform about disease severity.
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Iacobuzio-Donahue, Christine A., Jason Song, Giovanni Parmiagiani, Charles J. Yeo, Ralph H. Hruban, and Scott E. Kern. "Missense Mutations of MADH4." Clinical Cancer Research 10, no. 5 (March 1, 2004): 1597–604. http://dx.doi.org/10.1158/1078-0432.ccr-1121-3.
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Davies, Faith C. J., Jilly E. Hope, Fiona McLachlan, Grant F. Marshall, Laura Kaminioti-Dumont, Vesa Qarkaxhija, Francis Nunez, et al. "Recapitulation of the EEF1A2 D252H neurodevelopmental disorder-causing missense mutation in mice reveals a toxic gain of function." Human Molecular Genetics 29, no. 10 (March 11, 2020): 1592–606. http://dx.doi.org/10.1093/hmg/ddaa042.
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Abstract Heterozygous de novo mutations in EEF1A2, encoding the tissue-specific translation elongation factor eEF1A2, have been shown to cause neurodevelopmental disorders including often severe epilepsy and intellectual disability. The mutational profile is unusual; ~50 different missense mutations have been identified but no obvious loss of function mutations, though large heterozygous deletions are known to be compatible with life. A key question is whether the heterozygous missense mutations operate through haploinsufficiency or a gain of function mechanism, an important prerequisite for design of therapeutic strategies. In order both to address this question and to provide a novel model for neurodevelopmental disorders resulting from mutations in EEF1A2, we created a new mouse model of the D252H mutation. This mutation causes the eEF1A2 protein to be expressed at lower levels in brain but higher in muscle in the mice. We compared both heterozygous and homozygous D252H and null mutant mice using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. Although the proteomic analysis pointed to a loss of function for the D252H mutant protein, the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. Mice that are heterozygous for the missense mutation show no behavioural abnormalities but do have sex-specific deficits in body mass and motor function. The phenotyping of our novel mouse lines, together with analysis of molecular modelling and interacting proteins, suggest that the D252H mutation results in a gain of function.
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Leventer, Richard J., Carlos Cardoso, David H. Ledbetter, and William B. Dobyns. "LIS1 missense mutations cause milder lissencephaly phenotypes including a child with normal IQ." Neurology 57, no. 3 (August 14, 2001): 416–22. http://dx.doi.org/10.1212/wnl.57.3.416.
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Background: Classical lissencephaly is a disorder of neuroblast migration with most patients having mutations of either the LIS1 or DCX genes. Most patients with lissencephaly secondary to LIS1 mutations have a severe malformation consisting of generalized agyria and pachygyria. However, increasing experience suggests that the phenotypic spectrum is wider than previously thought.Methods: The authors describe the clinical and imaging features and mutation data of the five known patients with missense mutations of the LIS1 gene and emphasize one patient with normal intelligence.Results: Patients with a missense mutation of the LIS1 gene have a wider and milder spectrum of cortical malformations and clinical sequelae compared with patients with other mutation types.Conclusion: Milder and more variable phenotypes seen in patients with missense mutations of LIS1 are likely a consequence of suboptimal function of the mutant LIS1 protein, rather than complete loss of function of this protein. The authors suggest that the few patients found thus far with missense mutations of LIS1 results from an underascertainment of patients with more subtle malformations and that abnormalities of the LIS1 gene may account for a greater spectrum of neurologic problems in childhood than has previously been appreciated.
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Abuzenadah, Adel, Ashley Cartwright, Nawal Al-Shammari, Rachael Coyle, Michaela Eckert, Ahlam Al-Buhairan, Sarah Messenger, et al. "Identification and characterisation of mutations associated with von Willebrand disease in a Turkish patient cohort." Thrombosis and Haemostasis 110, no. 08 (2013): 264–74. http://dx.doi.org/10.1160/th13-02-0135.
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SummarySeveral cohort studies have investigated the molecular basis of von Willebrand disease (VWD); however, these have mostly focused on European and North American populations. This study aimed to investigate mutation spectrum in 26 index cases (IC) from Turkey diagnosed with all three VWD types, the majority (73%) with parents who were knowingly related. IC were screened for mutations using multiplex ligation-dependent probe amplification and analysis of all von Willebrand factor gene (VWF) exons and exon/intron boundaries. Selected missense mutations were expressed in vitro. Candidate VWF mutations were identified in 25 of 26 IC and included propeptide missense mutations in four IC (two resulting in type 1 and two in recessive 2A), all influencing VWF expression in vitro. Four missense mutations, a nonsense mutation and a small in-frame insertion resulting in type 2A were also identified. Of 15 type 3 VWD IC, 13 were homozygous and two compound heterozygous for 14 candidate mutations predicted to result in lack of expression and two propeptide missense changes. Identification of intronic breakpoints of an exon 17–18 deletion suggested that the mutation resulted from non-homologous end joining. This study provides further insight into the pathogenesis of VWD in a population with a high degree of consanguineous partnerships.
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Cron, Randy Q., Mingce Zhang, Remy R. Cron, Devin Absher, John M. Bridges, Amanda Schnell, Pavan K. Bhatraju, et al. "DOCK8 mutations in COVID-19 and MIS-C Cytokine Storm Syndrome." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 62.04. http://dx.doi.org/10.4049/jimmunol.206.supp.62.04.
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Abstract Background We recently identified DOCK8 as a novel gene associated with cytokine storm syndrome (CSS). Heterozygous missense mutations in DOCK8 diminish NK cell lytic function and contribute to increased pro-inflammatory cytokine production (CSS). CSS is a potential complication of COVID-19 with severe consequences. Children are at risk of a SARS-CoV-2 post-infectious CSS, multisystem inflammatory syndrome in children (MIS-C). Host genetic factors associated with COVID-19 CSS and MIS-C CSS are unknown. Methods To date, 16 adult patients enrolled in a COVID-19 CSS clinical trial at UAB had whole genome sequencing. Four (25%) had rare heterozygous DOCK8 mutations (3 missense, 1 intronic). A COVID-19 CSS adult patient in Seattle also had a DOCK8 missense mutation. In addition, DOCK8 missense mutations were identified in 5 children (UAB & Northwell) hospitalized with MIS-C. DOCK8 mutations, or wild-type (WT) sequence controls, were introduced into human NK-92 cells by FOAMY virus transduction. WT and mutant DOCK8-expressing NK-92 cells were incubated with K562 target cells and compared for cytolysis and degranulation (CD107a). Results One COVID-19 patient DOCK8 mutation (Gly523Arg) reduced NK cell degranulation by 30% and cytolysis by 23% (n=3). Similar studies of 3 MIS-C patients with DOCK8 missense mutations revealed up to 31% reduced NK cell degranulation and 48% reduction in cytolysis by 3 mutations (n=3). Two-way ANOVA analysis revealed statistically significant (p<0.05) differences in NK cell degranulation and lysis for 4 unique DOCK8 mutations. Conclusion Heterozygous DOCK8 missense mutations may contribute to severe COVID-19 and MIS-C CSS by partial dominant-negative effects yielding decreased NK cell cytolysis.
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Dai, Letian, John Clarke, Paula Bolton-Maggs, Geoffrey Savidge, Anwar Alhaq, and Michael Mitchell. "Characterisation of five factor XI mutations." Thrombosis and Haemostasis 97, no. 06 (2007): 884–89. http://dx.doi.org/10.1160/th06-12-0704.
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SummaryA large scale factor XI (FXI) mutation screening program identified a number of novel candidate mutations and previously reported mutations and polymorphisms. Five potential missense mutations were selected for further study; these included two novel missense mutations – Met-18Ile (p.Met1Ile) and Met102Thr (p.Met120Thr), two previously reported missense mutations – Tyr133Ser (Tyr151Ser) and Thr575Met (Thr593Met), and one amino acid substitution previously reported as a polymorphism – Arg378Cys (Arg396Cys). The substitutions were recreated by the site-directed mutagenesis of a FXI cDNA and stably expressed in a BHK-570 cell line. Subsequent analysis of both the conditioned media and cell lysates showed that three of the substitutions, Met-18Ile, Met102Thr andTyr133Ser, prevented secretion of the mutated protein from the transfected cell line, resulting in a cross-reactive material negative (CRM-) phenotype. The remaining two mutants, Thr575Met and Arg378Cys, secreted significant levels of FXI into the conditioned media; however, these mutant FXIs were shown to have negligible factor IX activation activity in an APTT based assay. These results confirmed all five of the missense mutations as being causative of factor XI deficiency, despite one having been previously reported as a polymorphism (Arg378Cys) and one (Tyr133Ser) as a mild mutation – FXI:C 38 U/dl in a homozygous patient.
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Mustafa, S., I. Pabinger, and C. Mannhalter. "Protein S deficiency type I: identification of point mutations in 9 of 10 families." Blood 86, no. 9 (November 1, 1995): 3444–51. http://dx.doi.org/10.1182/blood.v86.9.3444.bloodjournal8693444.
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We identified potentially causative mutations in the active protein S gene (PROS 1) by direct sequencing of PROS 1-specific polymerase chain reaction (PRC) products of all 15 exons, including exon-intron boundaries in 10 families with hereditary protein S deficiency type I. Seven different mutations were found in 9 of 10 families, including one frame shift mutation, a previously published splice site mutation (both occurring in two unrelated families), four missense mutations, and a stop codon at the beginning of exon 12. In family studies, cosegregation of the mutation with the disease could be demonstrated for five mutations; for two missense mutations, this was not possible due to limited family data. All seven mutations were the only abnormalities identified in the respective index patients and were absent in 44 to 62 normal individuals. Therefore, they most likely represent the causal gene defects. For five mutations, analysis of ectopic RNA could be performed. Mutant transcripts were present in the case of the frame shift and three of the missense mutations, while no mutant RNA could be detected in the case of the stop codon.
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Gong, Wen-yu, Fan-na Liu, Liang-hong Yin, and Jun Zhang. "Novel Mutations of COL4A5 Identified in Chinese Families with X-Linked Alport Syndrome and Literature Review." BioMed Research International 2021 (March 2, 2021): 1–10. http://dx.doi.org/10.1155/2021/6664973.
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Alport syndrome (AS) is an inherited kidney disease caused by defects in type IV collagen, which is characterized by hematuria, progressive nephritis or end-stage renal disease (ESRD), hearing loss, and occasionally ocular lesions. Approximately 80% of AS cases are caused by X-linked mutations in the COL4A5 gene. This study explored novel deletion and missense mutations in COL4A5 responsible for renal disorder in two Han Chinese families. In pedigree 1, the five male patients all had ESRD at a young age, while the affected female members only presented with microscopic hematuria. Whole exome sequencing and Sanger sequencing identified a novel frameshift deletion mutation (c.422_428del, p.Leu142Valfs∗11) in exon 7 of COL4A5. In pedigree 2, the 16-year-old male proband had elevated serum creatinine (309 μmol/L) without extrarenal manifestations, while his mother only manifested with hematuria. A missense mutation (c.476G>T, p.Gly159Val) was found in exon 9 of the COL4A5 gene. Neither of these mutations was present in the Exome Variant Server of the NHLBI-ESP database, nor was it found in the ExAC or 1000 Genomes databases. Through the literature review, it was found that male Chinese patients with X-linked AS carried COL4A5 deletion or missense mutations had a more severe phenotype than female patients, particularly in proteinuria and impaired renal function. Compared to male patients with missense mutations, patients in whom deletion mutations were found were more likely to progress to ESRD (15.4% vs. 36.0%,P=0.041). This study identified two novel COL4A5 mutations in Chinese families with X-linked AS, expanded the mutational spectrum of the COL4A5 gene, and presented findings that are significant for the screening and genetic diagnosis of AS.
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Uyanik, G., N. Elcioglu, J. Penzien, C. Gross, Y. Yilmaz, A. Olmez, E. Demir, et al. "Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome." Neurology 66, no. 7 (April 10, 2006): 1044–48. http://dx.doi.org/10.1212/01.wnl.0000204181.31175.8b.
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Background: Andermann syndrome (OMIM 218000) is an autosomal recessive motor-sensory neuropathy associated with developmental and neurodegenerative defects. The cerebral MRI reveals a variable degree of agenesis of the corpus callosum. Recently, truncating mutations of the KCC3 gene (also known as SLC12A6) have been associated with Andermann syndrome.Methods: The authors assessed clinically and genetically three isolated cases from Germany and Turkey with symptoms consistent with Andermann syndrome.Results: The authors detected four novel mutations within the KCC3 gene in their patients: two different truncating mutations in the first patient, a homozygous truncating mutation in the second, and a homozygous missense mutation in the third patient. In contrast to the classic phenotype of the Andermann syndrome linked to truncating KCC3 mutations the phenotype and the course of the disease linked to the missense mutation appeared to be different (i.e., showing additional features like diffuse and widespread white matter abnormalities).Conclusions: Not only truncating but also missense mutations of the KCC3 gene are associated with Andermann syndrome. Different types of KCC3 mutations may determine different clinical phenotypes.
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Guo, Zhiping, Linhua Yang, Xiuyu Qin, Xiue Liu, and Yaofang Zhang. "Spectrum of Molecular Defects in 216 Chinese Families With Hemophilia A: Identification of Noninversion Mutation Hot Spots and 42 Novel Mutations." Clinical and Applied Thrombosis/Hemostasis 24, no. 1 (January 5, 2017): 70–78. http://dx.doi.org/10.1177/1076029616687848.
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Hemophilia A (HA) is an X-linked bleeding disorder caused by heterogeneous mutations in the factor VIII gene ( F8). Our aim is to identify the causative mutations in a large HA cohort from China. We studied 216 unrelated HA families. Molecular analyses of F8 were performed using a combination of molecular techniques, including polymerase chain reaction, direct sequencing, and multiplex ligation-dependent probe amplification. The deleterious consequences of the unreported missense mutations were evaluated using various bioinformatics approaches. Causative mutations in F8 were identified in 209 families, intron 22 inversion (Inv22) was identified in 89 severe families, and intron 1 inversion (Inv1) was positive in 5 severe families; 95 mutations were detected among 115 noninversion families, of which 42 were novel, including 29 null variations and 13 missense mutations for which causality was demonstrated via bioinformatics. Among the 53 previously reported mutations, more nonsense (5 of 9) and missense (10 of 26) mutation sites were found to occur at Arginine (Arg) sites and multiple small deletions/insertions (5 of 10) located within the poly-A runs of the B domain. The majority of these sequence variants frequently recurred in the database. The odds ratios for the likelihood of developing inhibitors significantly increased in the presence of nonsense mutation. Our F8 defect spectrum was heterogeneous. Small deletions/insertions in the poly-A runs of the B domain and nonsense and missense mutations at Arg sites were identified as mutation hot spots. Nonsense mutation increased the risk of developing inhibitors.
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Phillips, John D., Tiffany L. Parker, Heidi L. Schubert, Frank G. Whitby, Christopher P. Hill, and James P. Kushner. "Functional consequences of naturally occurring mutations in human uroporphyrinogen decarboxylase." Blood 98, no. 12 (December 1, 2001): 3179–85. http://dx.doi.org/10.1182/blood.v98.12.3179.
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Abstract Functional consequences of 12 mutations—10 missense, 1 splicing defect, and 1 frameshift mutation—were characterized in the uroporphyrinogen decarboxylase (URO-D) gene found in Utah pedigrees with familial porphyria cutanea tarda (F-PCT). All but one mutation altered a restriction site in the URO-D gene, permitting identification of affected relatives using a combination of polymerase chain reaction and restriction enzyme digestion. In a bacterial expression system, 3 of the missense mutants were found in inclusion bodies, but 7 were expressed as soluble proteins. Enzymatic activity of soluble, recombinant mutant URO-D genes ranged from 29% to 94% of normal. URO-D mRNA levels in Epstein-Barr–virus transformed cells derived from patients were normal (with the exception of the frameshift mutation) even though protein levels were lower than normal, suggesting that missense mutations generally cause unstable URO-Ds in vivo. The crystal structures of 3 mutant URO-Ds were solved, and the structural consequences of the mutations were defined. All missense mutations reported here and by others were mapped to the crystal structure of URO-D, and structural effects were predicted. These studies define structural and functional consequences of URO-D mutations occurring in patients with F-PCT.
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SUCULARLI, CEREN. "Evaluation of cancer related missense mutations in CENPH." Acta Medica 50, no. 4 (October 30, 2019): 42–47. http://dx.doi.org/10.32552/2019.actamedica.385.
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Objective: CENPH, centromere protein H, is one of the constitutive kinetochore proteins. High expression of CENPH has been shown in various forms of cancers; however, studies searching the effect of CENPH mutations in cancers are limited. Therefore, the aim of this study is to investigate the potential effects of the missense mutations of CENPH that have been identified in different cancers.
Materials and Methods: Missense CENPH mutations, which have been observed in cancers, were downloaded from the COSMIC v89. The effect of missense mutations was predicted by using PredictSNP1.0. The protein structure of the CENPH protein was generated with I-TASSER and missense mutations were visualized on CENPH protein with UCSF Chimera. Structural effects of selected mutations were assessed with HOPE.
Results: 34 missense mutations were observed in human cancers. Of the 34 missense mutations 18 mutations were predicted as deleterious and 16 mutations were predicted as neutral with ranging expected accuracies. Predicted missense mutations showed a scattered pattern on 3D CENPH protein. Two of the predicted deleterious missense mutations with higher expected accuracy were further analyzed and assessed according to amino acid properties.
Conclusion: This study provided a systematic analysis and evaluation of missense mutations on a CENPH protein that have been observed in different cancers.
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Kapoor, Ritika R., Sarah E. Flanagan, Piers Fulton, Anupam Chakrapani, Bernadette Chadefaux, Tawfeg Ben-Omran, Indraneel Banerjee, Julian P. Shield, Sian Ellard, and Khalid Hussain. "Hyperinsulinism–hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype–phenotype correlations." European Journal of Endocrinology 161, no. 5 (November 2009): 731–35. http://dx.doi.org/10.1530/eje-09-0615.
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BackgroundActivating mutations in the GLUD1 gene (which encodes for the intra-mitochondrial enzyme glutamate dehydrogenase, GDH) cause the hyperinsulinism–hyperammonaemia (HI/HA) syndrome. Patients present with HA and leucine-sensitive hypoglycaemia. GDH is regulated by another intra-mitochondrial enzyme sirtuin 4 (SIRT4). Sirt4 knockout mice demonstrate activation of GDH with increased amino acid-stimulated insulin secretion.ObjectivesTo study the genotype–phenotype correlations in patients with GLUD1 mutations. To report the phenotype and functional analysis of a novel mutation (P436L) in the GLUD1 gene associated with the absence of HA.Patients and methodsTwenty patients with HI from 16 families had mutational analysis of the GLUD1 gene in view of HA (n=19) or leucine sensitivity (n=1). Patients negative for a GLUD1 mutation had sequence analysis of the SIRT4 gene. Functional analysis of the novel P436L GLUD1 mutation was performed.ResultsHeterozygous missense mutations were detected in 15 patients with HI/HA, 2 of which are novel (N410D and D451V). In addition, a patient with a normal serum ammonia concentration (21 μmol/l) was heterozygous for a novel missense mutation P436L. Functional analysis of this mutation confirms that it is associated with a loss of GTP inhibition. Seizure disorder was common (43%) in our cohort of patients with a GLUD1 mutation. No mutations in the SIRT4 gene were identified.ConclusionPatients with HI due to mutations in the GLUD1 gene may have normal serum ammonia concentrations. Hence, GLUD1 mutational analysis may be indicated in patients with leucine sensitivity; even in the absence of HA. A high frequency of epilepsy (43%) was observed in our patients with GLUD1 mutations.
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Talsness, Dana M., Joseph J. Belanto, and James M. Ervasti. "Disease-proportional proteasomal degradation of missense dystrophins." Proceedings of the National Academy of Sciences 112, no. 40 (September 21, 2015): 12414–19. http://dx.doi.org/10.1073/pnas.1508755112.
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The 427-kDa protein dystrophin is expressed in striated muscle where it physically links the interior of muscle fibers to the extracellular matrix. A range of mutations in the DMD gene encoding dystrophin lead to a severe muscular dystrophy known as Duchenne (DMD) or a typically milder form known as Becker (BMD). Patients with nonsense mutations in dystrophin are specifically targeted by stop codon read-through drugs, whereas out-of-frame deletions and insertions are targeted by exon-skipping therapies. Both treatment strategies are currently in clinical trials. Dystrophin missense mutations, however, cause a wide range of phenotypic severity in patients. The molecular and cellular consequences of such mutations are not well understood, and there are no therapies specifically targeting this genotype. Here, we have modeled two representative missense mutations, L54R and L172H, causing DMD and BMD, respectively, in full-length dystrophin. In vitro, the mutation associated with the mild phenotype (L172H) caused a minor decrease in tertiary stability, whereas the L54R mutation associated with a severe phenotype had a more dramatic effect. When stably expressed in mammalian muscle cells, the mutations caused steady-state decreases in dystrophin protein levels inversely proportional to the tertiary stability and directly caused by proteasomal degradation. Both proteasome inhibitors and heat shock activators were able to increase mutant dystrophin to WT levels, establishing the new cell lines as a platform to screen for potential therapeutics personalized to patients with destabilized dystrophin.
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Score, Joannah, Claire Hidalgo-Curtis, Amy V. Jones, Nils Winkelmann, Alison Skinner, Daniel Ward, Katerina Zoi, et al. "Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms." Blood 119, no. 5 (February 2, 2012): 1208–13. http://dx.doi.org/10.1182/blood-2011-07-367243.
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Abstract The polycomb repressive complex 2 (PRC2) is a highly conserved histone H3 lysine 27 methyltransferase that regulates the expression of developmental genes. Inactivating mutations of the catalytic component of PRC2, EZH2, are seen in myeloid disorders. We reasoned that the other 2 core PRC2 components, SUZ12 and EED, may also be mutational targets in these diseases, as well as associated factors such as JARID2. SUZ12 mutations were identified in 1 of 2 patients with myelodysplastic syndrome/myeloproliferative neoplasms with 17q acquired uniparental disomy and in 2 of 2 myelofibrosis cases with focal 17q11 deletions. All 3 were missense mutations affecting the highly conserved VEFS domain. Analysis of a further 146 myelodysplastic syndrome/myeloproliferative neoplasm patients revealed an additional VEFS domain mutant, yielding a total mutation frequency of 1.4% (2 of 148). We did not find mutations of JARID2 or EED in association with acquired uniparental disomy for chromosome 6p or 11q, respectively; however, screening unselected cases identified missense mutations in EED (1 of 148; 1%) and JARID2 (3 of 148; 2%). All 3 SUZ12 mutations tested and the EED mutation reduced PRC2 histone methyltransferase activity in vitro, demonstrating that PRC2 function may be compromised in myeloid disorders by mutation of distinct genes.
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Chen, Yuting, Haoyu Lu, Ning Zhang, Zefeng Zhu, Shuqin Wang, and Minghui Li. "PremPS: Predicting the impact of missense mutations on protein stability." PLOS Computational Biology 16, no. 12 (December 30, 2020): e1008543. http://dx.doi.org/10.1371/journal.pcbi.1008543.
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Computational methods that predict protein stability changes induced by missense mutations have made a lot of progress over the past decades. Most of the available methods however have very limited accuracy in predicting stabilizing mutations because existing experimental sets are dominated by mutations reducing protein stability. Moreover, few approaches could consistently perform well across different test cases. To address these issues, we developed a new computational method PremPS to more accurately evaluate the effects of missense mutations on protein stability. The PremPS method is composed of only ten evolutionary- and structure-based features and parameterized on a balanced dataset with an equal number of stabilizing and destabilizing mutations. A comprehensive comparison of the predictive performance of PremPS with other available methods on nine benchmark datasets confirms that our approach consistently outperforms other methods and shows considerable improvement in estimating the impacts of stabilizing mutations. A protein could have multiple structures available, and if another structure of the same protein is used, the predicted change in stability for structure-based methods might be different. Thus, we further estimated the impact of using different structures on prediction accuracy, and demonstrate that our method performs well across different types of structures except for low-resolution structures and models built based on templates with low sequence identity. PremPS can be used for finding functionally important variants, revealing the molecular mechanisms of functional influences and protein design. PremPS is freely available at https://lilab.jysw.suda.edu.cn/research/PremPS/, which allows to do large-scale mutational scanning and takes about four minutes to perform calculations for a single mutation per protein with ~ 300 residues and requires ~ 0.4 seconds for each additional mutation.
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Yang, Lihong, Yingyu Wang, Jianpin Zhou, Xiaoli Cheng, Xiuping Hao, Haixiao Xie, Yanhui Jin, and Mingshan Wang. "Identification of Genetic Defects Underlying FXII Deficiency in Four Unrelated Chinese Patients." Acta Haematologica 135, no. 4 (2016): 238–40. http://dx.doi.org/10.1159/000444209.
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Congenital factor XII (FXII) deficiency is a rare autosomal recessive disorder, characterized by a great variability in its clinical manifestations. In this study, we screened for mutations in the F12 gene of 4 unrelated patients with FXII coagulant activity <10% of that of normal human plasma. To investigate the molecular defects in these FXII-deficient patients, we performed FXII mutation screening. By sequencing all coding exons as well as flanking intronic regions of the F12 gene, 6 different mutations, including 3 missense mutations (Gly341Arg, Glu502Lys and Gly542 Ser), 1 insertion (7142insertC) and 2 deletions (5741-5742 delCA and 6753-6755delACA), were identified on the F12 gene. Three of them (Gly341Arg, 5741-5742delCA and 6753-6755delACA) are reported here for the first time. Computer-based algorithms predicted these missense mutations to be deleterious. This study has increased our knowledge of the mutational spectrum underlying FXII deficiency.
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Gąsior-Perczak, Danuta, Artur Kowalik, Krzysztof Gruszczyński, Agnieszka Walczyk, Monika Siołek, Iwona Pałyga, Sławomir Trepka, et al. "Incidence of the CHEK2 Germline Mutation and Its Impact on Clinicopathological Features, Treatment Responses, and Disease Course in Patients with Papillary Thyroid Carcinoma." Cancers 13, no. 3 (January 26, 2021): 470. http://dx.doi.org/10.3390/cancers13030470.
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The CHEK2 gene is involved in the repair of damaged DNA. CHEK2 germline mutations impair this repair mechanism, causing genomic instability and increasing the risk of various cancers, including papillary thyroid carcinoma (PTC). Here, we asked whether CHEK2 germline mutations predict a worse clinical course for PTC. The study included 1547 unselected PTC patients (1358 women and 189 men) treated at a single center. The relationship between mutation status and clinicopathological characteristics, treatment responses, and disease outcome was assessed. CHEK2 mutations were found in 240 (15.5%) of patients. A CHEK2 I157T missense mutation was found in 12.3%, and CHEK2 truncating mutations (IVS2 + 1G > A, del5395, 1100delC) were found in 2.8%. The truncating mutations were more common in women (p = 0.038), and were associated with vascular invasion (OR, 6.91; p < 0.0001) and intermediate or high initial risk (OR, 1.92; p = 0.0481) in multivariate analysis. No significant differences in these parameters were observed in patients with the I157T missense mutation. In conclusion, the CHEK2 truncating mutations were associated with vascular invasion and with intermediate and high initial risk of recurrence/persistence. Neither the truncating nor the missense mutations were associated with worse primary treatment response and outcome of the disease.
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Mitchell, Michael J., Letian Dai, John B. Clarke, Anwar Alhaq, and Geoffrey F. Savidge. "Characterisation of 6 Factor XI Missense Mutations." Blood 106, no. 11 (November 16, 2005): 1787. http://dx.doi.org/10.1182/blood.v106.11.1787.1787.
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Abstract Factor XI deficiency (MIM 264900) is an autosomal bleeding disorder of variable clinical severity. In contrast to haemophilia A or B the clinical symptoms do not correlate well with plasma levels of factor XI; it is therefore difficult to predict the bleeding tendency from either the factor level or the molecular defect. Causative mutations, outside of the Ashkenazi Jewish population, are highly heterogeneous, with 79 different mutations currently recorded on the Factor XI Deficiency Mutation Database (http://www.factorxi.com/), and this number being added to at a rapid rate. The identification of novel missense mutations leaves the dilemma as to whether these are causative or not. The in vitro expression of novel missense mutations is currently the preferred method for assigning causality. We have utilised site-directed mutagenesis and lipofectamine transfection to express novel factor XI missense mutations in a Baby Hamster Kidney cell line (BHK 570). Three novel /previously uncharacterised missense mutations, Met-18Ile, Met102Thr and Thr575Met, and a change previously reported as a polymorphism, Arg378Cys, were expressed in vitro. Two further missense mutations, on which expression data had been reported, were also expressed as expression negative (Tyr133Ser) and expression positive (Pro520Leu) controls, along with the wild-type FXI cDNA vector. A sandwich ELISA assay failed to detect factor XI antigen in the conditioned media of cell lines expressing the Met-18Ile, Met102Thr or the Tyr133Ser mutant FXI cDNAs but detected good FXI expression from the wild-type FXI cDNA. FXI antigen was detected in the cell lysates of all three cell lines, at similar levels to the wild-type cell line, demonstrating that factor XI was being synthesised in but not being secreted by these cell lines. Preliminary data for the Thr575Met, Arg378Cys and Pro520Leu cell lines shows that a significant amount of FXI antigen is being secreted into the conditioned media, with levels broadly similar for all three cell lines. However, levels in the wild-type cell line are approximately 6-fold higher. Further work is on-going to see whether this is a true reflection of secretion efficiency or the effect of differences in cell growth, plasmid incorporation etc. Levels of FXI antigen in cell lysates from these cell lines were broadly similar. Functional studies on these proteins is on-going. The Arg378Cys ‘mutation’, although previously reported as a polymorphism, was detected in a factor XI deficient father and daughter, with no other genetic variation detectable. Secretion of the Arg378Cys protein was surprising as the creation of a free Cysteine residue was expected to cause structural disruption resulting in a CRM- phenotype, as seen in the Arg308Cys and Trp501Cys mutants. We await the results of the function studies with interest. The Met-18Ile mutation was of particular interest as the mutation results in the loss of the initiator Methionine. Western blot analysis failed to detect any size difference between factor XI antigen recovered from cell lysates from the Met-18Ile and wild-type cell lines. We intend to purify the M-18I FXI protein and subject it to tandem MS analysis to try and determine the amnio acid sequence of this mutant protein.
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Ogata, Kyoichi, and Steven W. Pipe. "Most Factor VIII B Domain Missense Mutations Are Unlikely to Be Causative Mutations for Hemophilia A: Implications for Factor VIII Genetic Analysis." Blood 112, no. 11 (November 16, 2008): 513. http://dx.doi.org/10.1182/blood.v112.11.513.513.
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Abstract Hemophilia A results from the quantitative or qualitative deficiency of coagulation factor VIII (FVIII). FVIII is synthesized as a single-chain polypeptide of approximately 280 kDa with the domain structure A1-A2-B-A3-C1-C2. Whereas the A and C domains exhibit ~40% amino acid identity to each other and to the A and C domains of coagulation factor V, the B domain is not homologous to any known protein and is dispensable for FVIII cofactor activity. Missense mutations in the FVIII B domain have been described in patients with variable phenotypes of hemophilia A. According to the NCBI SNPs (single nucleotide polymorphism) database, 22 SNPs are reported within FVIII, 11 of which occur within the B domain. FVIII B domain variant D1241E has been reported as a missense mutation associated with mild or severe hemophilia A, yet this mutation is also present in the NCBI SNPs database. We hypothesize that D1241E and most other reported B domain missense mutations are not the causative mutation for hemophilia A in these patients but represent SNPs or otherwise non-pathologic mutations. To investigate this, we analyzed 7 B domain missense mutations that were previously found in hemophilia A patients (T751S, V993L, H1047Y, D1241E, T1353A, P1641L and S1669L). Comparative analysis showed that the amino acids at these positions are not conserved in all species and in some cases, the amino acid substitution reported in hemophilia patients is represented in the native sequence in other species. Analysis with PolyPhen Software showed that only H1047Y mutation was considered as “possibly damaging”, while the others were considered as “benign”. To investigate this further, we constructed seven plasmid vectors containing these B domain missense mutations. The synthesis and secretion of FVIII wild-type (WT) and these seven mutants were compared after transient DNA transfection into COS-1 monkey cells in vitro. Analysis of the FVIII clotting activity and antigen levels in the conditioned medium demonstrated that all mutants had FVIII activity and antigen levels similar to FVIII WT. Further, FVIII WT, H1047Y and D1241E mutants were introduced into a FVIII exon 16 knock-out mouse model of hemophilia A by hydrodynamic tailvein injection in vivo. The mouse plasma was analyzed at 24 hrs for activity and antigen expression. Mutants H1047Y and D1241E expressed at 211 mU/mL and 224 mU/mL activity with FVIII antigen levels of 97 ng/mL and 118 ng/mL, respectively, similar to FVIII WT. These results suggested that H1047Y and D1241E mutants did not lead to impairments in secretion or functional activity. We conclude that most missense mutations within the FVIII B domain would be unlikely to lead to severe hemophilia A and that the majority of such missense mutations represent polymorphisms or non-pathologic mutations. Investigators should search for additional potentially causative mutations elsewhere within the FVIII gene when B domain missense mutations are identified.
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Sun, Chong, Jie Song, Yanjun Jiang, Chongbo Zhao, Jiahong Lu, Yuxin Li, Yin Wang, et al. "Loss-of-function mutations in Lysyl-tRNA synthetase cause various leukoencephalopathy phenotypes." Neurology Genetics 5, no. 2 (April 2019): e565. http://dx.doi.org/10.1212/nxg.0000000000000316.
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ObjectiveTo expand the clinical spectrum of lysyl-tRNA synthetase (KARS) gene–related diseases, which so far includes Charcot-Marie-Tooth disease, congenital visual impairment and microcephaly, and nonsyndromic hearing impairment.MethodsWhole-exome sequencing was performed on index patients from 4 unrelated families with leukoencephalopathy. Candidate pathogenic variants and their cosegregation were confirmed by Sanger sequencing. Effects of mutations on KARS protein function were examined by aminoacylation assays and yeast complementation assays.ResultsCommon clinical features of the patients in this study included impaired cognitive ability, seizure, hypotonia, ataxia, and abnormal brain imaging, suggesting that the CNS involvement is the main clinical presentation. Six previously unreported and 1 known KARS mutations were identified and cosegregated in these families. Two patients are compound heterozygous for missense mutations, 1 patient is homozygous for a missense mutation, and 1 patient harbored an insertion mutation and a missense mutation. Functional and structural analyses revealed that these mutations impair aminoacylation activity of lysyl-tRNA synthetase, indicating that defective KARS function is responsible for the phenotypes in these individuals.ConclusionsOur results demonstrate that patients with loss-of-function KARS mutations can manifest CNS disorders, thus broadening the phenotypic spectrum associated with KARS-related disease.
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ÖZDEMİR, Mustafa, Şerif HAMİTOĞLU, Ferda ÖZLÜ, Hacer YAPICIOĞLU, Gülen GÜL MERT, and Mehmet SATAR. "The first living newborn case with 7706G˃A missense mutation: Alpers-Huttenlocher syndrome." Cukurova Medical Journal 47, no. 4 (December 28, 2022): 1780–83. http://dx.doi.org/10.17826/cumj.1170135.
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Alpers-Huttenlocher syndrome (AHS) is an uncommon autosomal recessive mitochondrial DNA depletion disease. The classic clinical triad of progressive developmental regression, liver degeneration, and seizures helps define the disorder, but a wide range of clinical expressions occur. The most common mutations in childhood have been identified in the cytochrome c oxidase Ⅰ and Ⅳ genes. The 7706G˃A missense mutation in the Cox Ⅱ gene was previously reported in one case after postmortem histological study. Consequently, our patient is the first patient diagnosed with AHS with a 7706G˃A missense mutation in the Cox Ⅱ gene while alive. We proposed that 7706G˃A missense mutation is rare and should be more lethal than other mutations that cause Alpers-Huttenlocher syndrome.
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Huang, Chein-Fuang, Lee-Yung Shih, Der-Cherng Liang, Sung-Tzu Liang, Jen-Fen Fu, Yu-Shu Shih, Chia-Ling Chang, Jo-Chuan Liu, Wen-Hsin Hsu, and Chang-Liang Lai. "High Frequency of C-Terminal Frame-Shift Mutations of RUNX1 Gene in De Novo AML with Partial Tandem Duplication of MLL." Blood 114, no. 22 (November 20, 2009): 3468. http://dx.doi.org/10.1182/blood.v114.22.3468.3468.
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Abstract Abstract 3468 Poster Board III-356 Background Transcription factor RUNX1 is essential for normal hematopoiesis. RUNX1 mutations, mainly at Runt homology domain (RHD), have been described in patients with AML-M0 and were rarely found in non-M0 AML. Aim We aimed to analyze the RUNX1 mutations in AML patients with partial tandem duplication of MLL (MLL-PTD) and to investigate the biological functions of the mutants detected. Patients and methods Bone marrow samples from 93 patients with MLL-PTD were analyzed for RUNX1 mutations. MLL-PTD was screened by Southern-blot analysis followed by RT-PCR or detected by real-time quantitative PCR. Mutational analysis of RUNX1 gene was performed by sequencing of all RT-PCR products amplified from exon 3 through exon 8. Each mutation was reconfirmed with alternative primers. The wild-type, all mutants of RUNX1 (except those truncated at RHD or silent) and pcDNA3.1 were transiently transfected into Cos-7 cells. Immunoblot analysis after immunoprecipitation with anti-FLAG RUNX1 antibody and electrophoretic mobility shift assay were used to determine the interaction with CBFβ and DNA-binding ability of the RUNX1 mutants. Dual luciferase assay system was used to analyze the transactivation potential of RUNX1 mutants in K562 cells. Results RUNX1 mutations were detected in 23 patients (24.7%) at diagnosis, with 3 patients carrying double mutations; 14 mutations were located in RHD (exons 3-5) and 12 at C-terminal region (exons 6-8). In addition, one patient acquired a C-terminal mutation at relapse. The patterns of 27 mutations consisted of 6 missense mutations, 3 nonsense mutations, 17 frame-shift mutations, and 1 silent mutation; all were heterozygous. Of the 3 patients with double mutations, clonal analysis showed that one patient had combined missense and frame-shift mutations on the same allele, the other patient had two missense mutations on different alleles, and another patient had a missense mutation and a silent mutation on the same allele. Functional analyses revealed significant difference among mutants. Two missense RUNX1 mutants at RHD (G108D and R174L) and all of the frame-shift mutants in the transactivation domain (TAD) ( S287fsX571, S295fsX571, L300fsX570, V333fsX574, I339fsX569 and P355fsX572) exhibited lack of DNA-binding ability and inhibited transactivation activity of wild-type RUNX1 in a dominant-negative effect. All frame-shift mutants distal to the TAD generated termination codons within the 3'-untranslated region (H377fsX565, Q388fsX572, L414fsX569, L414fsX567 and V425fsX576), they all retained the normal transactivation activity as the wild-type. R177X and R205W retained the ability of heterodimerization with CBFβ but they had markedly reduced DNA-binding and no transactivation potential without inhibitory effect on wild-type RUNX1. L183fsX185 could bind DNA but lacked transactivation activity. S114P and Q370R had normal transactivation activity. Conclusions Our results showed that patients with de novo AML with MLL-PTD had a high frequency of frame-shift mutations at C-terminal region of RUNX1; those within TAD had dominant-negative effects whereas those distal to TAD retained the normal transactivation potential. Supported by grants NHRI-EX96-9434SI, NSC97-2314-B-182 -011-MY3 and MMH-E-96009. Disclosures No relevant conflicts of interest to declare.
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Yuille, Martin R., Alison Condie, Chantelle D. Hudson, Paul S. Bradshaw, Elaine M. Stone, Estella Matutes, Daniel Catovsky, and Richard S. Houlston. "ATM mutations are rare in familial chronic lymphocytic leukemia." Blood 100, no. 2 (July 15, 2002): 603–9. http://dx.doi.org/10.1182/blood.v100.2.603.
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Abstract It is now recognized that a subset of B-cell chronic lymphocytic leukemia (CLL) is familial. The genetic basis of familial CLL is poorly understood, but recently germ line mutations in the Ataxia Telangiectasia (ATM) gene have been proposed to confer susceptibility to CLL. The evidence for this notion is, however, not unequivocal. To examine this proposition further we have screened the ATM gene for mutations in CLLs from 61 individuals in 29 families. Truncating ATM mutations, including a knownATM mutation, were detected in 2 affected individuals, but the mutations did not cosegregate with CLL in the families. In addition, 3 novel ATM missense mutations were detected. Common ATM missense mutations were not overrepresented. The data support previous observations that ATM mutation is associated with B-CLL. However, ATM mutations do not account for familial clustering of the disease.
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Neale, B. M. "Making Sense of Missense Mutations." Science Translational Medicine 5, no. 179 (April 3, 2013): 179ec57. http://dx.doi.org/10.1126/scitranslmed.3006205.
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Corso, Giovanni, Irene Feroce, Mattia Intra, Antonio Toesca, Francesca Magnoni, Manuela Sargenti, Paola Naninato, et al. "BRCA1/2 germline missense mutations." European Journal of Cancer Prevention 27, no. 3 (May 2018): 279–86. http://dx.doi.org/10.1097/cej.0000000000000337.
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Ozdemir, D., P. S. Hart, O. H. Ryu, S. J. Choi, M. Ozdemir-Karatas, E. Firatli, N. Piesco, and T. C. Hart. "MMP20 Active-site Mutation in Hypomaturation Amelogenesis Imperfecta." Journal of Dental Research 84, no. 11 (November 2005): 1031–35. http://dx.doi.org/10.1177/154405910508401112.
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The Amelogenesis Imperfecta (AI) are a group of clinically and genetically heterogeneous disorders that affect enamel formation. To date, mutations in 4 genes have been reported in various types of AI. Mutations in the genes encoding the 2 enamel proteases, matrix metalloproteinase 20 ( MMP20) and kallikrein 4 ( KLK4), have each been reported in a single family segregating autosomal-recessive hypomaturation AI. To determine the frequency of mutations in these genes, we analyzed 15 Turkish probands with autosomal-recessive hypomaturation AI for MMP20 and KLK4 gene mutations. No KLK4 mutations were found. A novel MMP20 mutation (g.16250T>A) was found in one family. This missense mutation changed the conserved active-site His226 residue of the zinc catalytic domain to Gln (p.H226Q). Zymogram analysis demonstrated that this missense mutation abolished MMP20 proteolytic activity. No MMP20 mutations were found in the remaining 14 probands, underscoring the genetic heterogeneity of hypomaturation AI.
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Hagiwara, Takeshi, Hiroshi Inaba, Shinichi Yoshida, Keiko Nagaizumi, Morio Arai, Hideji Hanabusa, and Katsuyuki Fukutake. "A Novel Mutation Glyl672→Arg in Type 2A and a Homozygous Mutation in Type 2B von Willebrand Disease." Thrombosis and Haemostasis 76, no. 02 (1996): 253–57. http://dx.doi.org/10.1055/s-0038-1650564.
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SummaryGenetic materials from 16 unrelated Japanese patients with von Willebrand disease (vWD) were analyzed for mutations. Exon 28 of the von Willebrand factor (vWF) gene, where point mutations have been found most frequent, was screened by various restriction-enzyme analyses. Six patients were observed to have abnormal restriction patterns. By sequence analyses of the polymerase chain-reaction products, we identified a homozygous R1308C missense mutation in a patient with type 2B vWD; R1597W, R1597Q, G1609R and G1672R missense mutations in five patients with type 2A; and a G1659ter nonsense mutation in a patient with type 3 vWD. The G1672R was a novel missense mutation of the carboxyl-terminal end of the A2 domain. In addition, we detected an A/C polymorphism at nucleotide 4915 with HaeIII. There was no particular linkage disequilibrium of the A/C polymorphism, either with the G/A polymorphism at nucleotide 4391 detected with Hphl or with the C/T at 4891 detected with BstEll.
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Gao, Shujuan, Min Lin, Yan Jin, Zhuona Wang, Yunqing Zhu, Guisheng Liu, and Xueyan Guo. "Three Novel Mutations of APC Gene Found in A Chinese Family with Familial Adenomatous Polyposis." Journal of Clinical and Nursing Research 6, no. 3 (May 30, 2022): 174–80. http://dx.doi.org/10.26689/jcnr.v6i3.3893.
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Objective: To identify the causative adenomatous polyposis coli (APC) gene defects associated with a pedigree of familial adenomatous polyposis (FAP). Methods: FAP was diagnosed based on clinical manifestations, family history, as well as endoscopic and pathological examinations. The blood samples of the FAP pedigree members, colonic polyp patients, and normal individuals were collected. Genomic DNA was then extracted from those samples. APC mutation analysis was conducted via direct polymerase chain reaction (PCR) sequencing. Results: Three synonymous mutations and a missense mutation were found: c.5034G>A (p.Gly1678Gly), c.5465T>A (p.Val1822Asp), c.5880G>A (p.Pro1960Pro), and c.5274T>G (p.Ser1758Ser). Among them, the homozygous mutation on APC gene c.5034G>A has been reported, while the other three mutations have not been reported in the Chinese Han population. Individuals with c.5465T>A (p.Val1822ASP) missense mutation eventually suffer from colon cancer and have poor prognosis. We found no mutation in patients with simple intestinal polyp and in normal individuals. In addition, there were homozygous and heterozygous mutations in different patients from the same family. Conclusion: Three new mutations of APC gene were firstly reported in Han population. The missense mutation of c.5465T>A (p.Val1822Asp) may be the cause of carcinogenesis in this FAP pedigree with poor prognosis.
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Tankovic, Jacques, Dominique Lamarque, Jean-Charles Delchier, Claude-James Soussy, Agnes Labigne, and Peter J. Jenks. "Frequent Association between Alteration of therdxA Gene and Metronidazole Resistance in French and North African Isolates of Helicobacter pylori." Antimicrobial Agents and Chemotherapy 44, no. 3 (March 1, 2000): 608–13. http://dx.doi.org/10.1128/aac.44.3.608-613.2000.
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ABSTRACT Mutations in the rdxA gene have been associated with the acquisition of resistance to metronidazole in Helicobacter pylori. This gene encodes an NADPH nitroreductase whose expression is necessary for intracellular activation of the drug. We wished to examine whether mutations in rdxA were present in resistant H. pylori isolates infecting either French or North African patients. We determined the complete nucleotide sequences of the rdxA genes from seven French and six North African patients infected with paired resistant and sensitive strains. Genotyping by random amplified polymorphic DNA analysis confirmed the close genetic relatedness of the susceptible and resistant isolates from individual biopsies. Eight French and five North African individual resistant strains were also studied. For the French strains, an alteration in rdxA most probably implicated in resistance was found in 10 cases (seven frameshift mutations, two missense mutations, and one deletion of 211 bp). One to three putative missense mutations were identified in four cases, and a missense mutation possibly not implicated in resistance was discovered in the last case. For the North African strains, an alteration inrdxA was found in eight cases (three frameshift mutations, three missense mutations, one deletion of 6 bp, and one insertion of a variant of IS605). Two strains contained putative missense mutations, and no change was observed in rdxA of the last strain. Thus, inactivation of the rdxA gene is frequently, but not always, associated with resistance to metronidazole in French and North African clinical isolates of H. pylori. In addition, a variety of alterations of rdxA are associated with the resistant phenotype.
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Lee, Jiyun, Hana Kim, Antonio Gualberto, Catherine Rose Scholz, and Se Hoon Park. "Tipifarnib, a farnesyltransferase inhibitor, for metastatic urothelial carcinoma harboring HRAS mutations." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 5086. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.5086.
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5086 Background: Tipifarnib is a farnesyltransferase inhibitor known to block RAS signaling and attenuate cancer cell proliferation. We tested the activity and safety of tipifarnib in patients with previously treated urothelial carcinoma (UC) carrying HRAS mutations. Methods: In a prospective phase II clinical trial, genetic screening was performed in 224 UC patients; those with missense HRAS mutations or STK11:rs2075606 received study treatment. Eligible patients received oral tipifarnib 900 mg twice daily on days 1–7 and 15–21 of 28-d treatment cycles. The primary endpoint was progression-free survival at 6 mo (PFS6). With two-stage design, at least 18 patients were required. Results: Among the 224 patients screened, we found 16 (7%) missense HRAS mutations (G13R, 7; Q61R, 4; G12S, 3; G12C, 2) and 104 (46%) STK11: rs2075606 carriers. In 21 patients enrolled, 14 and 7 patients had HRAS mutations and STK11:rs2075606, respectively. The most frequent adverse events included fatigue and hematologic toxicities. With a median follow-up of 28 months, 4 patients (19%) reached PFS6: 3 had missense HRAS mutations and one patient, enrolled as a STK11 carrier, had HRAS frameshift insertions at H27fs and H28fs rendering a nonsense HRAS mutation. Response rate was 24% (4 missense and one nonsense frameshift HRAS mutation); no response observed in UC patients with wild type HRAS tumors. Conclusions: Oral tipifarnib showed a manageable safety profile and encouraging anti-tumor efficacy against treatment-refractory UC containing HRAS mutations. Clinical trial information: NCT02535650 .
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Park, Edward, Leiqian Tai, Peggy Nakagawa, Loan Hsieh, and Diane J. Nugent. "Novel Missense Mutations Associated with FXIII Deficiency and Bleeding." Blood 114, no. 22 (November 20, 2009): 4201. http://dx.doi.org/10.1182/blood.v114.22.4201.4201.
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Abstract Abstract 4201 Introduction Factor XIII deficient patients may present at any age, with a variety of bleeding symptoms, poor wound healing, and in females, frequent miscarriages. Factor XIII (FXIII) is a transglutaminase enzyme that was first discovered as a clotting protein in the coagulation cascade, but it is now understood that it cross-links proteins in the plasma, vascular matrix, endothelial cells, platelets and monocytes. In addition to maintaining normal hemostasis, FXIII plays a role in atherosclerosis, wound healing, inflammation, and pregnancy. FXIII circulates in plasma as a tetramer protein (FXIII-A2B2) held together by non-covalent bonds. FXIII has two catalytic A subunits (FXIII-A2) of 83kd and two non-catalytic B subunits or carrier subunits (FXIII-B2) of 79kd. Mutations have been identified in almost every exon of the FXIIIA subunit and often are unique to a particular cohort or family with Factor XIII deficiency. Our center has been characterizing patients with FXIII deficiency and has an IRB approved study to characterize bleeding phenotype in relation to genotype or mutational analysis. As part of this effort, we have identified 3 novel missense mutations, which we have not found in the FXIII database (<www.f13-database.de>) or in previous publications. Methods After obtaining informed consent, venous blood was collected in EDTA tubes for DNA isolation, PCR and ultimately DNA sequencing. DNA was isolated using QIAamp DNA Blood Midi Kit (Qiagen, Germantown, MD). Customary PCR was used to amplify the 15 exons for subunit A and the 12 exons for subunit B, using sequence specific primers based on previous publication and created to initiate outside of the encoding sequence. The nucleotide sequencing of amplified products was obtained via ABI 3730 DNA Analyzer (UCLA Sequencing and Genotyping Core). Results All three novel mutations were found in three, separate, unrelated individuals, with FXIII deficiency diagnosed early in life with a moderate to severe bleeding. Using the methods described above, the DNA sequencing and analysis for all exons for both the A and B subunits revealed three novel mutations, two on exon 12 subunit A and one on exon 10 subunit A. Patient 1 has a novel missense mutation in exon 10 at the 427 amino acid position, changing the aspartic acid into an asparagine (Asp427Asn) in the catalytic core. Patient 2 and 3 each had a unique mutation in exon 12. Exon 12 covers the transition from the catalytic core region and the Barrel 1 region of the FXIIIA molecule thus including portions of each functional region. Patient 2: An exon 12 missense mutation in aa 501 resulting in a change from glycine to an arginine (Gly501Arg) still in the catalytic core region. Patient 3 also had a mutation in exon 12 but in position 576 resulting in an amino acid change from threonine to methionine (Thr576Met) now in the Barrel 1 region. Patient 2 also had a missense mutation that has been previously reported in exon 3 (Arg77His) in the β-sandwich region. Three new missense mutations have been identified in patients with severe Factor XIII deficiency and a bleeding disorder. Previous reports of other point mutations in the FXIIIA catalytic core and barrel 1 regions have also been described in association with a hemorrhagic state in deficient patients. Ongoing protein expression studies will aid in our understanding of how these single amino acid substitutions result in such a serious bleeding diathesis. Disclosures: No relevant conflicts of interest to declare.
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Yadegari, Hamideh, Julia Driesen, Anna Pavlova, Arijit Biswas, Hans-Jörg Hertfelder, and Johannes Oldenburg. "Mutation distribution in the von Willebrand factor gene related to the different von Willebrand disease (VWD) types in a cohort of VWD patients." Thrombosis and Haemostasis 108, no. 10 (2012): 662–71. http://dx.doi.org/10.1160/th12-02-0089.
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SummaryVon Willebrand disease (VWD) is the most common inherited bleeding disorder caused by quantitative or qualitative defects of the von Willebrand factor (VWF). VWD is classified into three types – type 1 (partial quantitative deficiencies), type 2 (qualitative defects) and type 3 (complete deficiency of VWF). In this study we explored genotype and phenotype characteristics of patients with VWD with the aim of dissecting the distribution of mutations in different types of VWD. One hundred fourteen patients belonging to 78 families diagnosed to have VWD were studied. Mutation analysis was performed by direct sequencing of the VWF. Large deletions were investigated by multiplex ligation-dependent probe amplification (MLPA) analysis. The impact of novel candidate missense mutations and potential splice site mutations was predicted by in silico assessments. We identified mutations in 66 index patients (IPs) (84.6%). Mutation detection rate was 68%, 94% and 94% for VWD type 1, 2 and 3, respectively. In total, 68 different putative mutations were detected comprising 37 missense mutations (54.4%), 10 small deletions (14.7%), two small insertions (2.9%), seven nonsense mutations (10.3%), five splice-site mutations (7.4%), six large deletions (8.8%) and one silent mutation (1.5%). Twenty-six of these mutations were novel. Furthermore, in type 1 and type 2 VWD, the majority of identified mutations (74% vs. 88.1%) were missense substitutions while mutations in type 3 VWD mostly caused null alleles (82%). Genotyping in VWD is a helpful tool to further elucidate the pathogenesis of VWD and to establish the relationship between genotype and phenotype.
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Clark, Graeme R., Marco Sciacovelli, Edoardo Gaude, Diana M. Walsh, Gail Kirby, Michael A. Simpson, Richard C. Trembath, et al. "Germline FH Mutations Presenting With Pheochromocytoma." Journal of Clinical Endocrinology & Metabolism 99, no. 10 (October 1, 2014): E2046—E2050. http://dx.doi.org/10.1210/jc.2014-1659.
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Abstract Context: At least a third of the patients with pheochromocytoma (PCC) or paraganglioma (PGL) harbor an underlying germline mutation in a known PCC/PGL gene. Mutations in genes (SDHB, SDHD, SDHC, and SDHA) encoding a component of the tricarboxylic acid cycle, succinate dehydrogenase (SDH), are a major cause of inherited PCC and PGL. SDHB mutations are also, albeit less frequently, associated with inherited renal cell carcinoma. Inactivation of SDH and another tricarboxylic acid cycle component, fumarate hydratase (FH), have both been associated with abnormalities of cellular metabolism, responsible for the activation of hypoxic gene response pathways and epigenetic alterations (eg, DNA methylation). However, the clinical phenotype of germline mutations in SDHx genes and FH is usually distinct, with FH mutations classically associated with hereditary cutaneous and uterine leiomyomatosis and renal cell carcinoma, although recently an association with PCC/PGL has been reported. Objective and Design: To identify potential novel PCC/PGL predisposition genes, we initially undertook exome resequencing studies in a case of childhood PCC, and subsequently FH mutation analysis in a further 71 patients with PCC, PGL, or head and neck PGL. Results: After identifying a candidate FH missense mutation in the exome study, we then detected a further candidate missense mutation (p.Glu53Lys) by candidate gene sequencing. In vitro analyses demonstrated that both missense mutations (p.Cys434Tyr and p.Glu53Lys) were catalytically inactive. Conclusions: These findings 1) confirm that germline FH mutations may present, albeit rarely with PCC or PGL; and 2) extend the clinical phenotype associated with FH mutations to pediatric PCC.
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Lee, Yejin, Hong Zhang, Figen Seymen, Youn Jung Kim, Yelda Kasimoglu, Mine Koruyucu, James P. Simmer, Jan C. C. Hu, and Jung-Wook Kim. "Novel KLK4 Mutations Cause Hypomaturation Amelogenesis Imperfecta." Journal of Personalized Medicine 12, no. 2 (January 24, 2022): 150. http://dx.doi.org/10.3390/jpm12020150.
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Amelogenesis imperfecta (AI) is a group of rare genetic diseases affecting the tooth enamel. AI is characterized by an inadequate quantity and/or quality of tooth enamel and can be divided into three major categories: hypoplastic, hypocalcified and hypomaturation types. Even though there are some overlapping phenotypes, hypomaturation AI enamel typically has a yellow to brown discoloration with a dull appearance but a normal thickness indicating a less mineralized enamel matrix. In this study, we recruited four Turkish families with hypomaturation AI and performed mutational analysis using whole exome sequencing. These analyses revealed two novel homozygous mutations in the KLK4 gene: a nonsense mutation in exon 3 (NM_004917.4:c.170C>A, p.(Ser57*)) was found in families 1, 2 and 3 and a missense mutation in exon 6 (c.637T>C, p.(Cys213Arg)) in family 4. Functional analysis showed that the missense mutation transcript could not translate the mutant protein efficiently or generated an unstable protein that lacked functional activity. The two novel inactivating KLK4 mutations we identified caused a hypomaturation AI phenotype similar to those caused by the four previously described KLK4 nonsense and frameshift mutations. This study improves our understanding of the normal and pathologic mechanisms of enamel formation.
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Jeyaprakash, A., R. Das Gupta, and R. Kolodner. "Saccharomyces cerevisiae pms2 mutations are alleles of MLH1, and pms2-2 corresponds to a hereditary nonpolyposis colorectal carcinoma-causing missense mutation." Molecular and Cellular Biology 16, no. 6 (June 1996): 3008–11. http://dx.doi.org/10.1128/mcb.16.6.3008.
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A number of mutant Saccharomyces cerevisiae strains having phenotypes consistent with defects in DNA mismatch repair have been described, but not all have been extensively characterized. In this study we demonstrate that the pms2-1 and pms2-2 alleles arise from missense mutations in the MLH1 gene which inactivate MLH1. One of these alleles, pms2-2, causes the same amino acid substitution in a highly conserved region of the known MutL homologs as that caused by a proposed missense mutation observed in a Swedish hereditary nonpolyposis colorectal carcinoma kindred. This observation supports the functional significance of missense mutations found in hereditary nonpolyposis colorectal carcinoma kindreds and indicates that in some cases S. cerevisiae can serve as a useful model system for the analysis of such mutations.
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Gale, Rosemary E., Katarina Lamb, Christopher Allen, Dima El-Sharkawi, Cassandra Stowe, Sarah Jenkinson, Steven Tinsley, et al. "The Impact of Different DNMT3A Mutations on Outcome in Younger Adults with Acute Myeloid Leukemia." Blood 124, no. 21 (December 6, 2014): 67. http://dx.doi.org/10.1182/blood.v124.21.67.67.
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Abstract DNMT3A mutations (DNMT3AMUT) are recurrent in AML. They predominate in patients with intermediate-risk (IR) cytogenetics and are often co-incident with FLT3ITD and NPM1MUT. Their prognostic impact is unclear. Most reports suggest they are associated with a worse outcome, but a large study including 1060 younger adult IR patients found that DNMT3AMUT had no significant impact on survival endpoints. Variable results have also been reported for different FLT3/NPM1 subgroups. Missense mutations at R882 in exon 23 occur in ≈65% of patients, but other missense and truncation mutations occur throughout the gene, mainly in exons 13-23. There is limited information on the prognostic impact of the different mutations, although they may have differing functional consequences. We therefore screened exons 13-23 in DNA samples from 914 younger adult AML patients (median age 43 years) with IR cytogenetics treated on UK MRC trials and evaluated outcome according to type of DNMT3Amutation. Overall, 278 mutations were detected in 272 (30%) patients; 175 (64%) had R882 missense mutations, 59 (22%) other missense mutations, 35 (13%) truncations or in-frame deletions; 3 (1%) had 2 mutations of differing types. Median R882 mutant level in 172 mutated cases was 47% (range 15-85%), consistent with a heterozygous mutation in most cells. Patients with DNMT3AMUT were significantly older than those with DNMT3A wild-type (DNMT3AWT) (P<.0001), more likely to be female (P=.004), have a higher presenting WBC (P<.0001), and a normal rather than abnormal karyotype (P<.0001). The presence of DNMT3AMUT positively correlated with FLT3ITD (P=.0003) and NPM1MUT (P<.0001) and negatively correlated with CEBPAMUT (P<.0001). Patients with R882 mutations had significantly higher WBC (P=.005) and correlation with NPM1MUT (P=.01) than non-R882 mutated patients; non-R882 missense mutated patients had higher WBC (P=.05) and non-significant higher co-incidence with FLT3ITD than those with truncations. Presence of DNMT3AMUT was associated with a poorer prognosis, but this difference was only seen if the results were analyzed separately according to NPM1 genotype, where DNMT3AMUT was associated with higher cumulative incidence of relapse (CIR) than DNMT3AWT in cases with NPM1MUT (49% vs 40%, P=.01) and NPM1WT (61% vs 58%, P=.5) genotype. Similarly, DNMT3AMUT patients had worse overall survival (OS) than DNMT3AWT patients with NPM1MUT (38% vs 50%, P=.008) and NPM1WT (15% vs 25%, P=.09) genotype. This statistical anomaly is an example of Simpson’s paradox. It results from the strong co-incidence of DNMT3A and NPM1 mutations with opposing prognostic associations that mask the effect seen separately when the groups are combined. Although the differences were smaller for NPM1WT cases, tests for heterogeneity showed that the impact of a DNMT3A mutation did not differ between NPM1MUT and NPM1WT for either CIR or OS, nor between the 4 genotypes defined by the combination of NPM1 and FLT3ITD genotypes. In multivariable analysis including age, WBC, NPM1 and FLT3ITD, DNMT3AMUT was a significant adverse risk factor for CIR (HR=1.27, CI=1.01-1.61; P=.04), and showed a trend for being adverse for OS (HR=1.19, CI=.98-1.45; P=.08). When outcome was considered according to the type of mutation (R882, other missense or truncations), for the NPM1MUT genotype cases CIR was highest in R882 and other missense cases (51%, 50%) and truncation cases were similar to DNMT3AWT (35%, 40%). For NPM1WT, CIR was highest in R882 cases (76%), similar in other missense and DNMT3AWT cases (55%, 58%) and lowest in truncation cases (40%). Consistent with this data, for NPM1MUT genotype, OS was lowest in R882 and other missense cases (35%, 38%), better in DNMT3AWT (50%) and highest in truncation cases (57%). For NPM1WT, OS was lowest in R882 cases (11%), and similar in DNMT3AWT, other missense and truncation cases (25%, 21%, 18% respectively). These data suggest that screening cannot be limited to the hotspot R882 mutations and that cases with missense mutations should be treated as poor risk, including those patients currently considered as favorable risk such as NPM1MUTFLT3WT. Conversely, truncation mutations have a different functional impact from missense mutations, more likely to result in haploinsufficiency than a dominant-negative effect, and these cases should be considered as equivalent to DNMT3AWT for prognostication and selection of therapy in 1st remission. Disclosures No relevant conflicts of interest to declare.