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Captur, Gabriella, Eloisa Arbustini, Petros Syrris, Dina Radenkovic, Ben O'Brien, William J. Mckenna y James C. Moon. "Lamin mutation location predicts cardiac phenotype severity: combined analysis of the published literature". Open Heart 5, n.º 2 (octubre de 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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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, n.º 4 (13 de noviembre de 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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Gábos, Gabriella, Dumitru Moldovan, Daniela Dobru, Enikő Mihály, Noémi Bara, Valentin Nădășan, Adina Hutanu y 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, n.º 3 (1 de julio de 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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Kim, Soo-Hyun, Soo Young Choi, Sung-Eun Lee, Yun Jeong Oh, Jin-Eok Park, Hae Lyun Yoo, Hye-Rim Jeon, Eun-Jung Jang y Dong-Wook Kim. "Kinetics Of Low-Level Mutant Clones Detected By Subcloning and Sequencing In Tyrosine Kinase Inhibitor Resistant CML". Blood 122, n.º 21 (15 de noviembre de 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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Nguyen, Thi Kim Lien, Van Dem Pham, Thu Huong Nguyen, Trung Kien Pham, Thi Quynh Huong Nguyen y Huy Hoang Nguyen. "Three Novel Mutations in the NPHS1 Gene in Vietnamese Patients with Congenital Nephrotic Syndrome". Case Reports in Genetics 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/2357282.
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Congenital nephrotic syndrome, a rare and severe disease, is inherited as an autosomal recessive trait. The disease manifests shortly after birth and occurs predominantly in families of Finnish origin but has now been observed in all countries and races. Mutations in the NPHS1 gene, which encodes nephrin, are the main causes of congenital nephrotic syndrome in patients. In this study, we report the first mutational analysis of the NPHS1 gene in three unrelated children from three different Vietnamese families. These patients were examined and determined to be suffering from congenital nephrotic syndrome in the Department of Pediatrics, Vietnam National Hospital of Pediatrics. All 29 exons and exon-intron boundaries of NPHS1 were analyzed by PCR and DNA sequencing. Genetic analysis of the NPHS1 gene revealed one compound heterozygous variant p.Glu117Lys, one heterozygous missense mutation p.Asp310Asn, and one heterozygous frame-shifting mutation (c.3250_3251insG causing p.Val1084Glyfs⁎12) in patient 1. In patient 2, one heterozygous variant p.Glu117Lys and one novel heterozygous missense mutation p.Ser324Ala were identified. Finally, a novel missense mutation p.Arg802Leu and a novel nonsense mutation (c.2442C>G causing p.K792⁎) were identified in patient 3.
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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, n.º 3 (septiembre de 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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Musumeci, Antonino, Francesco Calì, Carmela Scuderi, Mirella Vinci, Girolamo Aurelio Vitello, Sebastiano Antonino Musumeci, Valeria Chiavetta et al. "Identification of a Novel Missense Mutation of POLR3A Gene in a Cohort of Sicilian Patients with Leukodystrophy". Biomedicines 10, n.º 9 (14 de septiembre de 2022): 2276. http://dx.doi.org/10.3390/biomedicines10092276.
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Recessive mutations in the POLR3A gene cause POLR3-HLD (the second-most-common form of childhood-onset hypomyelinating leukodystrophy), a neurodegenerative disorder featuring deficient cerebral myelin formation. To date, more than 140 POLR3A (NM_007055.3) missense mutations are related to the pathogenesis of POLR3-related leukodystrophy and spastic ataxia. Herein, in a cohort of five families from Sicily (Italy), we detected two cases of patients affected by POLR3-related leukodystrophy, one due to a compound heterozygous mutation in the POLR3A gene, including a previously undescribed missense mutation (c.328A > G (p.Lys110Glu)). Our study used an in-house NGS gene panel comprising 41 known leukodystrophy genes. Successively, we used a predictive test supporting the missense mutation as causative of disease, thus this mutation can be considered “Likely Pathogenic” and could be as a new pathogenetic mutation of the POLR3A gene causing a severe form of POLR3-HLD.
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Prophet, Malshundria, Kun Xiao, Theodore Stewart Gourdin, Rebecca J. Nagy, Lesli Ann Kiedrowski, Elisa Ledet, Guru Sonpavde, A. Oliver Sartor y Michael B. Lilly. "Detection of actionable BRAF missense mutations by ctDNA-based genomic analysis in prostate cancer." Journal of Clinical Oncology 36, n.º 6_suppl (20 de febrero de 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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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, n.º 10 (11 de marzo de 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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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, n.º 45 (27 de octubre de 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 y 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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ÖZDEMİR, Mustafa, Şerif HAMİTOĞLU, Ferda ÖZLÜ, Hacer YAPICIOĞLU, Gülen GÜL MERT y Mehmet SATAR. "The first living newborn case with 7706G˃A missense mutation: Alpers-Huttenlocher syndrome". Cukurova Medical Journal 47, n.º 4 (28 de diciembre de 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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Hagiwara, Takeshi, Hiroshi Inaba, Shinichi Yoshida, Keiko Nagaizumi, Morio Arai, Hideji Hanabusa y Katsuyuki Fukutake. "A Novel Mutation Glyl672→Arg in Type 2A and a Homozygous Mutation in Type 2B von Willebrand Disease". Thrombosis and Haemostasis 76, n.º 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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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, n.º 11 (16 de noviembre de 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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Leventer, Richard J., Carlos Cardoso, David H. Ledbetter y William B. Dobyns. "LIS1 missense mutations cause milder lissencephaly phenotypes including a child with normal IQ". Neurology 57, n.º 3 (14 de agosto de 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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Kapoor, Ritika R., Sarah E. Flanagan, Piers Fulton, Anupam Chakrapani, Bernadette Chadefaux, Tawfeg Ben-Omran, Indraneel Banerjee, Julian P. Shield, Sian Ellard y Khalid Hussain. "Hyperinsulinism–hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype–phenotype correlations". European Journal of Endocrinology 161, n.º 5 (noviembre de 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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Gao, Shujuan, Min Lin, Yan Jin, Zhuona Wang, Yunqing Zhu, Guisheng Liu y Xueyan Guo. "Three Novel Mutations of APC Gene Found in A Chinese Family with Familial Adenomatous Polyposis". Journal of Clinical and Nursing Research 6, n.º 3 (30 de mayo de 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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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, n.º 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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Rae, Julie, Deborah Noack, Paul G. Heyworth, Beverly A. Ellis, John T. Curnutte y Andrew R. Cross. "Molecular analysis of 9 new families with chronic granulomatous disease caused by mutations in CYBA, the gene encoding p22phox". Blood 96, n.º 3 (1 de agosto de 2000): 1106–12. http://dx.doi.org/10.1182/blood.v96.3.1106.015k44_1106_1112.
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Chronic granulomatous disease is a rare inherited disorder caused by nonexistent or severely decreased phagocyte superoxide production that results in a severe defect in host defense and consequent predisposition to microbial infection. The enzyme responsible for generating the superoxide, NADPH oxidase, involves at least 5 protein components. The absence of, or a defect in, any 1 of 4 of these proteins (p22phox, p47phox, p67phox, or gp91phox) gives rise to the known types of chronic granulomatous disease. One of the rarest forms of the disease is due to defects in the CYBA gene encoding p22phox, which together with gp91phox forms flavocytochromeb558, the catalytic core of NADPH oxidase. To date, only 9 kindreds with p22phoxdeficiency have been described in the literature comprising 10 mutant alleles. Four polymorphisms in the CYBA gene have also been reported. Here we describe 9 new, unrelated kindreds containing 12 mutations, 9 of which are novel. In addition, we report 3 new polymorphisms. The novel mutations are (a) deletion of exons 2 and 3, (b) a missense mutation in exon 3 (T155→C), (c) a splice site mutation at the 5′ end of intron 3, (d) a missense mutation in exon 2 (G74→T), (e) a nonsense mutation in exon 1 (G26→A), (f) a missense mutation in exon 4 (C268→T), (g) a frameshift in exon 3 due to the insertion of C at C162, (h) a nonsense mutation in exon 2 (G107→A), and (i) a missense mutation in exon 2 (G70→A).
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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, n.º 7 (10 de abril de 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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Phillips, John D., Tiffany L. Parker, Heidi L. Schubert, Frank G. Whitby, Christopher P. Hill y James P. Kushner. "Functional consequences of naturally occurring mutations in human uroporphyrinogen decarboxylase". Blood 98, n.º 12 (1 de diciembre de 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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Guo, Zhiping, Linhua Yang, Xiuyu Qin, Xiue Liu y 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, n.º 1 (5 de enero de 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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Hawthorne, Valerie Stone y Dihua Yu. "PI3K: Missense mutation motivates malignancy". Cancer Biology & Therapy 3, n.º 8 (agosto de 2004): 776–77. http://dx.doi.org/10.4161/cbt.3.8.1031.
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Lee, Jae-Bong, Chae-Kyoung Yoo, Eun-Ji Jung, Jung-Hye Hwang, Bo-Young Seo, Byeong-Woo Kim, Hyun-Tae Lim, Jung-Gyu Lee, In-Cheol Cho y Hee-Bok Park. "A missense mutation (c.1963A". Molecular Biology Reports 39, n.º 10 (5 de julio de 2012): 9291–97. http://dx.doi.org/10.1007/s11033-012-1679-8.
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Nakae, Jun, Shuji Abe, Toshihiro Tajima, Nozomi Shinohara, Mari Murashita, Yutaka Igarashi, Satoshi Kusuda, Junzou Suzuki y Kenji Fujieda. "Three Novel Mutations and a De Novo Deletion Mutation of the DAX-1 Gene in Patients with X-Linked Adrenal Hypoplasia Congenita". Journal of Clinical Endocrinology & Metabolism 82, n.º 11 (1 de noviembre de 1997): 3835–41. http://dx.doi.org/10.1210/jcem.82.11.4342.
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The DAX-1 [DSS (dosage sensitive sex)-AHC critical region on the X, gene 1] gene is responsible for X-linked adrenal hypoplasia congenita (AHC). However, DAX-1 protein structure-function relationships are not well understood. Identification of missense mutations may help to reveal these relationships. We analyzed the DAX-1 gene from seven patients in six kindreds with X-linked AHC and identified one frameshift mutation, two missense mutations, and three deletion mutations. Case 1 had a 388delAG frameshift mutation, inducing a premature stop codon at position 70. Case 2 had a missense mutation, Lys382Asn, which encodes an asparagine (Asn) for lysine (Lys) at position 382. Sibling cases of 3-1 and 3-2 had a missense mutation of Trp291Cys, which encodes a substitution of cysteine (Cys) for tryptophan (Try) at position 291. The tryptophan (Trp) at position 291 and lysine (Lys) at position 382 in human DAX-1 protein are highly conserved among other related orphan nuclear receptor superfamily members. Cases 4, 5, and 6 showed deletion mutation. In case 6, a de novo deletion mutation was revealed by both southern hybridization and polymerase chain reaction (PCR) of a GGAA tetranucleotide tandem repeat. These findings suggest that: 1) Trp at position 291 and Lys at position 382, located in the C-terminal presumptive ligand binding domain, are important to the functional role of the DAX-1 protein in adrenal embryogenesis and/or in hypothalamic-pituitary activity; and 2) molecular analysis of the DAX-1 gene may help genetic counseling, even in cases with deletion mutation, because a detection of de novo deletion may exclude another affected or carrier child.
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Fadiga, Lúcia, Mariana Lavrador, Nuno Vicente, Luísa Barros, Catarina I. Gonçalves, Asma Al-Naama, Luis R. Saraiva y Manuel C. Lemos. "A Novel FGFR1 Missense Mutation in a Portuguese Family with Congenital Hypogonadotropic Hypogonadism". International Journal of Molecular Sciences 23, n.º 8 (17 de abril de 2022): 4423. http://dx.doi.org/10.3390/ijms23084423.
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Congenital hypogonadotropic hypogonadism (CHH) is a rare reproductive endocrine disorder characterized by complete or partial failure of pubertal development and infertility due to deficiency of the gonadotropin-releasing hormone (GnRH). CHH has a significant clinical heterogeneity and can be caused by mutations in over 30 genes. The aim of this study was to investigate the genetic defect in two siblings with CHH. A woman with CHH associated with anosmia and her brother with normosmic CHH were investigated by whole exome sequencing. The genetic studies revealed a novel heterozygous missense mutation in the Fibroblast Growth Factor Receptor 1 (FGFR1) gene (NM_023110.3: c.242T>C, p.Ile81Thr) in the affected siblings and in their unaffected father. The mutation affected a conserved amino acid within the first Ig-like domain (D1) of the protein, was predicted to be pathogenic by structure and sequence-based prediction methods, and was absent in ethnically matched controls. These were consistent with a critical role for the identified missense mutation in the activity of the FGFR1 protein. In conclusion, our identification of a novel missense mutation of the FGFR1 gene associated with a variable expression and incomplete penetrance of CHH extends the known mutational spectrum of this gene and may contribute to the understanding of the pathogenesis of CHH.
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Mustafa, S., I. Pabinger y C. Mannhalter. "Protein S deficiency type I: identification of point mutations in 9 of 10 families". Blood 86, n.º 9 (1 de noviembre de 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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Ivaskevicius, Vytautas, Arijit Biswas, Anne Thomas, Ramin Tehranchi y Johannes Oldenburg. "Genetic Background in Patients with Severe Factor XIII A-Subunit Deficiency Treated with Recombinant FXIII". Blood 120, n.º 21 (16 de noviembre de 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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Rae, Julie, Deborah Noack, Paul G. Heyworth, Beverly A. Ellis, John T. Curnutte y Andrew R. Cross. "Molecular analysis of 9 new families with chronic granulomatous disease caused by mutations in CYBA, the gene encoding p22phox". Blood 96, n.º 3 (1 de agosto de 2000): 1106–12. http://dx.doi.org/10.1182/blood.v96.3.1106.
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Abstract Chronic granulomatous disease is a rare inherited disorder caused by nonexistent or severely decreased phagocyte superoxide production that results in a severe defect in host defense and consequent predisposition to microbial infection. The enzyme responsible for generating the superoxide, NADPH oxidase, involves at least 5 protein components. The absence of, or a defect in, any 1 of 4 of these proteins (p22phox, p47phox, p67phox, or gp91phox) gives rise to the known types of chronic granulomatous disease. One of the rarest forms of the disease is due to defects in the CYBA gene encoding p22phox, which together with gp91phox forms flavocytochromeb558, the catalytic core of NADPH oxidase. To date, only 9 kindreds with p22phoxdeficiency have been described in the literature comprising 10 mutant alleles. Four polymorphisms in the CYBA gene have also been reported. Here we describe 9 new, unrelated kindreds containing 12 mutations, 9 of which are novel. In addition, we report 3 new polymorphisms. The novel mutations are (a) deletion of exons 2 and 3, (b) a missense mutation in exon 3 (T155→C), (c) a splice site mutation at the 5′ end of intron 3, (d) a missense mutation in exon 2 (G74→T), (e) a nonsense mutation in exon 1 (G26→A), (f) a missense mutation in exon 4 (C268→T), (g) a frameshift in exon 3 due to the insertion of C at C162, (h) a nonsense mutation in exon 2 (G107→A), and (i) a missense mutation in exon 2 (G70→A).
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Ozdemir, D., P. S. Hart, O. H. Ryu, S. J. Choi, M. Ozdemir-Karatas, E. Firatli, N. Piesco y T. C. Hart. "MMP20 Active-site Mutation in Hypomaturation Amelogenesis Imperfecta". Journal of Dental Research 84, n.º 11 (noviembre de 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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Chen, Chia-Hsiang, Yu-Shu Huang, Ding-Lieh Liao, Cheng-Yi Huang, Chia-Heng Lin y Ting-Hsuan Fang. "Identification of Rare Mutations of Two Presynaptic Cytomatrix Genes BSN and PCLO in Schizophrenia and Bipolar Disorder". Journal of Personalized Medicine 11, n.º 11 (21 de octubre de 2021): 1057. http://dx.doi.org/10.3390/jpm11111057.
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Schizophrenia and bipolar disorder are severe mental disorders with a major component of genetic factors in their etiology. Rare mutations play a significant role in these two disorders, and they are highly heterogeneous and personalized. Identification of personalized mutations is essential for the establishment of molecular diagnosis, providing insight into pathogenesis and guiding the personalized treatment for each affected patient. We conducted whole-genome sequencing analysis of families with schizophrenia and bipolar disorder to search for their genetic underpinnings. This report identified a rare missense mutation Arg1087Gln of BSN (bassoon presynaptic cytomatrix protein) co-segregating with schizophrenia in a family with multiple affected members. Furthermore, we identified the rare missense mutation Ser1535Leu of PCLO (piccolo presynaptic cytomatrix protein) in two sisters with bipolar disorder and another rare missense mutation, His5142Arg in PCLO, in a patient with schizophrenia. These three missense mutations were very rare and were predicted to be pathogenic. The BSN and PCLO genes encode two structurally related proteins of the presynaptic cytomatrix at the active zone that regulates neurotransmission at the presynaptic neuronal terminal. Our findings suggest the involvement of the presynaptic matrix in the pathogenesis of schizophrenia and bipolar disorder, and BSN and PCLO are the risk genes for schizophrenia and bipolar disorder.
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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, n.º 5 (2 de febrero de 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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Cai, Bi-He, Yun-Chien Hsu, Fang-Yu Yeh, Yu-Rou Lin, Rui-Yu Lu, Si-Jie Yu, Jei-Fu Shaw et al. "P63 and P73 Activation in Cancers with p53 Mutation". Biomedicines 10, n.º 7 (23 de junio de 2022): 1490. http://dx.doi.org/10.3390/biomedicines10071490.
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The members of the p53 family comprise p53, p63, and p73, and full-length isoforms of the p53 family have a tumor suppressor function. However, p53, but not p63 or p73, has a high mutation rate in cancers causing it to lose its tumor suppressor function. The top and second-most prevalent p53 mutations are missense and nonsense mutations, respectively. In this review, we discuss possible drug therapies for nonsense mutation and a missense mutation in p53. p63 and p73 activators may be able to replace mutant p53 and act as anti-cancer drugs. Herein, these p63 and p73 activators are summarized and how to improve these activator responses, particularly focusing on p53 gain-of-function mutants, is discussed.
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Menke, Leonie A., Marc Engelen, Mariel Alders, Vincent J. J. Odekerken, Frank Baas y Jan M. Cobben. "Recurrent GNAO1 Mutations Associated With Developmental Delay and a Movement Disorder". Journal of Child Neurology 31, n.º 14 (29 de septiembre de 2016): 1598–601. http://dx.doi.org/10.1177/0883073816666474.
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In 2 unrelated patients with axial hypotonia, developmental delay and a hyperkinetic movement disorder, a missense mutation was found in codon 209 of the GNAO1 gene. From the still scarce literature on GNAO1 mutations, a clear genotype-phenotype correlation emerged. From the 26 patients reported thus far, 12 patients had epileptic encephalopathy, and 14 had a developmental delay and a hyperkinetic movement disorder. All but 1 of the latter patients had missense mutations in GNAO1 codon 209 or 246, which thus appear to be mutation hotspots. At least 2 sibling pairs showed that the recurrence risk after 1 affected child with a GNAO1 mutation might be relatively high (5-15%), due to apparent gonadal mosaicism in the parents.
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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, n.º 2 (abril de 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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Miller, Amber, Laura Cattaneo, Yan W. Asmann, Esteban Braggio, Jonathan J. Keats, Daniel Auclair, Sagar Lonial, The MMRF CoMMpass Network, Stephen J. Russell y A. Keith Stewart. "Correlation Between Somatic Mutation Burden, Neoantigen Load and Progression Free Survival in Multiple Myeloma: Analysis of MMRF CoMMpass Study". Blood 128, n.º 22 (2 de diciembre de 2016): 193. http://dx.doi.org/10.1182/blood.v128.22.193.193.
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Abstract Introduction Tumor specific somatic mutations can potentially influence patient response to targeted immunotherapies. Since somatic mutations generate neoantigens, novel tumor-specific peptides can be processed, loaded into MHC class I molecules, and presented to T-cells as potentially immunogenic targets. Indeed, both somatic mutation burden and neoantigen burden have been correlated with responsiveness to checkpoint inhibitor blockade in highly mutagenic advanced melanoma and lung cancer. However, correlation of response with mutation and neoantigen burden has not been reported for cancers of lower characteristic mutational burden such as multiple myeloma (MM). Indeed early results of checkpoint inhibitors in MM have been underwhelming. We therefore wished to better understand the mutation and neoantigen landscape of MM patients as it relates to responsiveness to current and future therapies. Materials/Methods Somatic mutation burden, neoantigen load, and response to therapy was obtained using interim data from theCoMMpassstudy (NCT01454297), a study by the Multiple Myeloma Research Foundation that collects longitudinal clinical and molecular data on 1,000 newly diagnosed MM patients from baseline through treatment and disease progression. Next-generation exome sequencing data was used to call somatic mutations andbioinformaticallydetermine patient specific HLA type. Neoantigen binding affinity was predicted for all unique patient specific somatic missense mutation and HLA allele combinations using a well validated neural network and machine learning based algorithm. Binding affinity of the corresponding non-mutated peptide was also predicted to identify mutated neoantigens witha high binding affinity while the wild type counterpart has low predicted binding affinity. Results For 627 patients with available sequencing and clinical data, mutation and neoantigen profiles were created. Within this population, the mean overall canonical somatic mutation load was 405.84 (s=608.55) mutations per patient. These mutations included 38,222 unique missense mutations in 12,994 genes. The mean somatic missense mutation load was 64.51(s=95.29) mutations per patient including immunoglobulin genes (52.70, s=94.85 excluding immunoglobulins). There was a positive linear correlation between mutation burden and neoantigen burden. The mean neoantigen load using thresholds of mutant peptide binding affinity (half maximal inhibitory concentration, IC50) less than 500nM was 69.57 (s=124.76) neoantigens (58.53, s=123.58 excluding immunoglobulins). Limiting binding affinity of wild type peptide sequence to greater than 500nM decreased the mean neoantigen load to 23.84 (s=53.55) neoantigens (20.74, s=53.28 excluding immunoglobulins). Progression free survival (PFS) following induction therapy was used to determine correlates of mutation burden excluding immunoglobulin mutations with response. Kaplan-Meier survival analysis revealed significantly shorter PFS time in patients with greater than average tumor somatic missense mutation load (N=126) relative to those with less than average mutation load (49.1% vs. 73.0% PFS at 2yrs, p=0.0055, Figure 1) Similarly, patients with greater than average neoantigen load (N=164) had significantly shorter PFS relative to those with less than average neoantigen load (48.0% vs. 74.2% PFS at 2yrs, p=0.00259, Figure 2). Moreover, patients with both high mutation and neoantigen load (N=85) had significantly shorter PFS relative to those with less than average mutation and neoantigen load (45.3% vs. 72% PFS at 2yrs, p= 0.0168). Conclusion While mutation and neoantigen load has been correlated with response to targeted immunotherapies in highly mutated solid tumors, we report here a negative correlation between mutation, neoantigen load and MM patient survival. This indicates that a high mutation andneoantigen load negatively impacts survival of myeloma patients under current standard of care. It is hypothesized that this is because current treatments fail to recruit T cell immunity necessary to exploit tumor neoantigens fundamental to immune-mediated killing of cancer cells. This presents an encouraging basis for pursuing targeted and personalized immunotherapies for multiple myeloma, especially for patients with a higher mutational burden. PFS and mutation load. PFS and mutation load. PFS and neoantigen load. PFS and neoantigen load. Disclosures Lonial: BMS: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Onyx: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Onyx: Consultancy; Novartis: Consultancy; BMS: Consultancy; Millenium: Consultancy; Merck: Consultancy.
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Huang, Hao, Dong-Bo Ding, Liang-Liang Fan, Jie-Yuan Jin, Jing-Jing Li, Shuai Guo, Ya-qin Chen y Rong Xiang. "Whole-exome sequencing identifies a Novel SCN5A mutation (C335R) in a Chinese family with arrhythmia". Cardiology in the Young 28, n.º 5 (6 de febrero de 2018): 688–91. http://dx.doi.org/10.1017/s1047951117002980.
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AbstractBackgroundSCN5A encodes sodium-channel α-subunit Nav1.5. The mutations of SCN5A can lead to hereditary cardiac arrhythmias such as the long-QT syndrome type 3 and Brugada syndrome. Here we sought to identify novel mutations in a family with arrhythmia.MethodsGenomic DNA was isolated from blood of the proband, who was diagnosed with atrial flutter. Illumina Hiseq 2000 whole-exome sequencing was performed and an arrhythmia-related gene-filtering strategy was used to analyse the pathogenic genes. Sanger sequencing was applied to verify the mutation co-segregated in the family.Results and conclusionsA novel missense mutation in SCN5A (C335R) was identified, and this mutation co-segregated within the affected family members. This missense mutation was predicted to result in amplitude reduction in peak Na+ current, further leading to channel protein dysfunction. Our study expands the spectrum of SCN5A mutations and contributes to genetic counselling of families with arrhythmia.
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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, n.º 3 (26 de enero de 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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MONKAWA, TOSHIAKI, ISAO KURIHARA, KAZUO KOBAYASHI, MATSUHIKO HAYASHI y TAKAO SARUTA. "Novel Mutations in Thiazide-Sensitive Na-Cl Cotransporter Gene of Patients with Gitelman's Syndrome". Journal of the American Society of Nephrology 11, n.º 1 (enero de 2000): 65–70. http://dx.doi.org/10.1681/asn.v11165.
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Abstract. Gitelman's syndrome (GS) is an autosomal recessive disorder characterized by metabolic alkalosis, hypokalemia, hypomagnesemia, and hypocalciuria that has recently been reported to be linked to thiazide-sensitive Na-Cl cotransporter (TSC) gene mutations. In this study, possible mutations in the TSC gene of six Japanese patients clinically diagnosed with GS were investigated. Twenty-six exons encoding TSC were amplified by PCR and then completely sequenced by the direct sequencing method. Patient A showed a missense mutation of Arg 642 to Cys on the paternal allele and a missense mutation of Val 578 to Met and a 2-bp deletion (nucleotide 2543-2544) on the maternal allele. This deletion results in a frameshift that alters codon 837 to encode a stop signal rather than phenylalanine, and it is predicted to lead to loss of the latter half of the intracellular carboxy terminus. In the second family, two affected sisters, patients B and C, had a homozygous missense mutation of Thr 180 to Lys. Both of their parents, who are consanguineously married, have a heterozygous Thr180Lys mutation. Patient D has a homozygous mutation Thr180Lys, which is the same as the second family. Haplotype analysis indicates that patients B and C are not related to patient D. In patients E and F, we could identify only one mutant allele; Ala569Glu and Leu849His, respectively. All of the mutations identified are novel except for the Arg642Cys mutation, which has been found in a Japanese GS patient. Although further in vitro study is required to prove that the mutations are responsible for GS, it is possible that Thr180Lys and Arg642Cys mutations might be common mutations in Japanese GS.
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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, n.º 1_Supplement (1 de mayo de 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 y Michael Mitchell. "Characterisation of five factor XI mutations". Thrombosis and Haemostasis 97, n.º 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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Chen, JinLan, BuYun Li, YiFeng Yang, JianGuo Hu, TianLi Zhao, YiBo Gong y ZhiPing Tan. "Mutations of the TGFBR2 gene in Chinese patients with Marfan-related syndrome". Clinical & Investigative Medicine 33, n.º 1 (1 de febrero de 2010): 14. http://dx.doi.org/10.25011/cim.v33i1.11833.
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Purpose: Transforming growth factor beta receptors II gene (TGFBR2) mutations associated with Marfan syndrome and Marfan-associated disorders have been investigated. However, such studies are limited in China. To obtain more information about TGFBR2 mutations, we analyzed 6 unrelated Chinese patients with Marfan-associated disorders and without ocular manifestation. Methods: The genomic DNA from blood leukocytes of these 6 patients and their relatives was isolated, and the entire coding region of TGFBR2 was amplified using PCR. We determined the sequence of TGFBR2 with the ABI 3100 Genetic Analyzer. Results: Three mutations were identified in TGFBR2. Two mutations were associated with Loeys-Dietz syndrome (LDS), which were distributed as following: one missense mutation R528C (caused by a 1582C > T substitution) and one polymorphism T315M (a rare SNP). The third mutation was a novel silent mutation associated with MFS2, which was K291K caused by an 873 C > T substitution. Conclusions: The TGFBR2 gene missense mutations are possibly causative mutations of Loeys-Dietz syndrome. This result suggests an increase in the mutation spectrum of Marfan-related disorders in China and possibly world-wide.
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Liu, Ji-Shi, Liang-Liang Fan, Hao Zhang, Xiaoxian Liu, Hao Huang, Li-Jian Tao, Kun Xia y Rong Xiang. "Whole-Exome Sequencing Identifies Two Novel TTN Mutations in Chinese Families with Dilated Cardiomyopathy". Cardiology 136, n.º 1 (20 de agosto de 2016): 10–14. http://dx.doi.org/10.1159/000447422.
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Objectives: Dilated cardiomyopathy (DCM) is a leading cause of sudden cardiac death. So far, only 127 mutations of Titin(TTN) have been reported in patients with different phenotypes such as isolated cardiomyopathies, purely skeletal muscle phenotypes or complex overlapping disorders of muscles. Methods: We applied whole-exome sequencing (WES) to investigate cardiomyopathy patients and a cardiomyopathy-related gene-filtering strategy was used to analyze the disease-causing mutations. Sanger sequencing was applied to confirm the mutation cosegregation in the affected families. Results: A nonsense mutation (c.12325C>T/p.R4109X) and a missense mutation (c.17755G>C/p.G5919R) of TTN were identified in 2 Chinese DCM families, respectively. Both mutations were cosegregated in all affected members of both families. The nonsense mutation is predicted to result in a truncated TTN protein and the missense mutation leads to a substitution of glycine by arginine. Both variants may cause the structure changes of titin protein. Conclusions: We employed WES to detect the mutations of DCM patients and identified 2 novel mutations. Our study expands the spectrum of TTN mutations and offers accurate genetic testing information for DCM patients who are still clinically negative.
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Frayling, Ian M., Victor-Felix Mautner, Rick van Minkelen, Roope A. Kallionpaa, Safiye Aktaş, Diana Baralle, Shay Ben-Shachar et al. "Breast cancer risk in neurofibromatosis type 1 is a function of the type of NF1 gene mutation: a new genotype-phenotype correlation". Journal of Medical Genetics 56, n.º 4 (10 de diciembre de 2018): 209–19. http://dx.doi.org/10.1136/jmedgenet-2018-105599.
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BackgroundNeurofibromatosis type 1 (NF1) predisposes to breast cancer (BC), but no genotype-phenotype correlations have been described.MethodsConstitutional NF1 mutations in 78 patients with NF1 with BC (NF1-BC) were compared with the NF1 Leiden Open Variation Database (n=3432).ResultsNo cases were observed with whole or partial gene deletions (HR 0.10; 95% CI 0.006 to 1.63; p=0.014, Fisher’s exact test). There were no gross relationships with mutation position. Forty-five (64.3%; HR 6.4–83) of the 70 different mutations were more frequent than expected (p<0.05), while 52 (74.3%; HR 5.3–83) were significant when adjusted for multiple comparisons (adjusted p≤0.125; Benjamini-Hochberg). Higher proportions of both nonsense and missense mutations were also observed (adjusted p=0.254; Benjamini-Hochberg). Ten of the 11 missense cases with known age of BC occurred at <50 years (p=0.041). Eighteen cases had BRCA1/2 testing, revealing one BRCA2 mutation.DiscussionThese data strongly support the hypothesis that certain constitutional mutation types, and indeed certain specific variants in NF1 confer different risks of BC. The lack of large deletions and excess of nonsenses and missenses is consistent with gain of function mutations conferring risk of BC, and also that neurofibromin may function as a dimer. The observation that somatic NF1 amplification can occur independently of ERBB2 amplification in sporadic BC supports this concept. A prospective clinical-molecular study of NF1-BC needs to be established to confirm and build on these findings, but regardless of NF1 mutation status patients with NF1-BC warrant testing of other BC-predisposing genes.
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Hsu, Hung-Chih, Jeng-Fu You, Shu-Jen Chen, Hua-Chien Chen, Chien-Yuh Yeh, Wen-Sy Tsai, Hsin-Yuan Hung, Tsai-Sheng Yang, Nina Lapke y Kien Thiam Tan. "TP53 DNA Binding Domain Mutations Predict Progression-Free Survival of Bevacizumab Therapy in Metastatic Colorectal Cancer". Cancers 11, n.º 8 (30 de julio de 2019): 1079. http://dx.doi.org/10.3390/cancers11081079.
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(1) Background: Bevacizumab-based regimens are a standard treatment for metastatic colorectal cancer (mCRC) patients, however meaningful clinical biomarkers for treatment benefit remain scarce. (2) Methods: Tumor samples from 36 mCRC patients treated with bevacizumab-based chemotherapy underwent comprehensive genomic profiling. Alterations in frequently altered genes and important signaling pathways were correlated with progression-free survival (PFS). (3) Results: Overall genetic alteration analysis of investigated genes and pathways did not identify promising new predictors of PFS. However, when considering mutation subtypes, TP53 DNA binding domain (DBD) missense mutations were associated with prolonged PFS (HR, 0.41; 95% CI, 0.13−0.65; p = 0.005). In contrast, TP53 truncating mutations were associated with short PFS (HR, 2.95; 95% CI, 1.45−27.50; p = 0.017). Importantly, neither TP53 mutation subtype was associated with overall response rate. In multivariate analysis, TP53 DBD missense mutations remained an independent PFS predictor (HR, 0.31; 95% CI, 0.13–0.77; p = 0.011). The other genetic factor independently associated with PFS were PTPRT/PTPRD deleterious alterations, which we previously identified in a screen for biomarkers of bevacizumab response. (4) Conclusions: TP53 DBD missense mutations may predict prolonged PFS in mCRC patients treated with bevacizumab-based therapy. Analyses of TP53 mutations as clinical biomarkers should take the biological impact of different mutation subtypes into consideration to improve patient stratification.
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Girolami, Antonio, Elisabetta Cosi, Silvia Ferrari y Bruno Girolami. "Prothrombin: Another Clotting Factor After FV That Is Involved Both in Bleeding and Thrombosis". Clinical and Applied Thrombosis/Hemostasis 24, n.º 6 (24 de abril de 2018): 845–49. http://dx.doi.org/10.1177/1076029618770741.
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Clotting factor defects are usually associated with bleeding. About 2 decades ago, 2 polymorphisms, one of FII (G20210A) and another of FV (Arg506Gln), have been shown to be associated with prothrombotic state and venous thrombosis. As a consequence, FII and FV could be considered both as prohemorrhagic factors and prothrombotic conditions. Recently, it has been shown that missense mutations in the prothrombin gene of amino acid Arg596 of exon 14 to Leu596, Gln596, or Trp596 caused the appearance of a thrombophilic state and venous thrombosis. These mutated FII are not associated with bleeding, but only with venous thrombosis. Furthermore, they are all heterozygotes for the mutations. No missense mutation associated with thrombosis has been discovered so far for FV. As a consequence, the prothrombotic activity of FII is the result of a polymorphism and of a missense mutation, whereas that of FV derives only from a polymorphism. The observation that a clotting factor defect may be associated with both bleeding or venous thrombosis depending on the site of the mutation has caused an extensive reevaluation of the blood clotting mechanism.
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Gong, Wen-yu, Fan-na Liu, Liang-hong Yin y Jun Zhang. "Novel Mutations of COL4A5 Identified in Chinese Families with X-Linked Alport Syndrome and Literature Review". BioMed Research International 2021 (2 de marzo de 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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Manabe, J., R. Arya, H. Sumimoto, T. Yubisui, AJ Bellingham, DM Layton y Y. Fukumaki. "Two novel mutations in the reduced nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase gene of a patient with generalized type, hereditary methemoglobinemia". Blood 88, n.º 8 (15 de octubre de 1996): 3208–15. http://dx.doi.org/10.1182/blood.v88.8.3208.bloodjournal8883208.
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Hereditary methemoglobinemia due to reduced nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase (b5R) deficiency is classified into two types, an erythrocyte (type I) and a generalized (type II). We investigated the b5R gene of a patient with type II from a white United Kingdom (UK) family and found that the patient was a compound heterozygote for two novel mutations. The first mutation was a C-to-A transversion changing codon 42 (TAC: Tyr) to a stop codon in the one allele. From this mutant allele, the product without the catalytic portion of the enzyme is generated. The second one was a missense mutation at codon 95 (CCC-->CAC) in the other allele with the result that Pro changed to His within the flavin adenine dinucleotide (FAD)-binding domain of the enzyme. To characterize effects of this missense mutation on the enzyme function, we compared glutathione S-transferase (GST)-fused b5R with the GST-fused mutant enzyme with the codon 95 missense mutation (P95H) expressed in Escherichia coll. The mutant enzyme showed less catalytic activity, less thermostability, and a greater susceptibility to trypsin than did the normal counterpart. The absorption spectrum of the mutant enzyme in the visual region differed from that of the wild-type. These results suggest that this amino acid substitution influences both secondary structure and catalytic activity of the enzyme. The compound heterozygosity for the nonsense and the missense mutations apparently caused hereditary methemoglobinemia type II in this patient.
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Havali, Cengiz, Sevil Dorum, Yılmaz Akbaş, Orhan Görükmez y Tugba Hirfanoglu. "Two different missense mutations of PEX genes in two similar patients with severe Zellweger syndrome: an argument on the genotype-phenotype correlation". Journal of Pediatric Endocrinology and Metabolism 33, n.º 3 (26 de marzo de 2020): 437–41. http://dx.doi.org/10.1515/jpem-2019-0194.
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AbstractBackgroundPeroxisomal biogenesis disorders (PBDs) include a miscellaneous group of diseases which cause serious multisystem disease. Mutations of 13 different PEX genes lead to PBDs including Zellweger syndrome (ZS). Different types of mutations of PEX1 and PEX10 genes are correlated with broad-range phenotypes of PBDs.Case presentationPatient 1 is a 4-month-old boy who was affected by myoclonic seizures, poor oral feeding since birth. The patient was hypotonic and had hepatosplenomegaly. Patient 2 is a 2-month-old boy who presented with decreased movement, severe hypotonia and failure to thrive. The laboratory studies of the patients revealed increased plasma very-long-chain fatty acids (VLCFAs). The genetic analyses of patient 1 demonstrated the first homozygous missense mutation in the PEX10 gene. A novel homozygous missense mutation was found in the PEX1 gene in patient 2.ConclusionsThis report highlights that the detected homozygous missense mutations of PEX10 and PEX1 genes and the substitutions of specific amino acids lead to the severe form of PBDs.
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Sakuma, Naoko, Hideaki Moteki, Hela Azaiez, Kevin T. Booth, Masahiro Takahashi, Yasuhiro Arai, A. Eliot Shearer et al. "Novel PTPRQ Mutations Identified in Three Congenital Hearing Loss Patients With Various Types of Hearing Loss". Annals of Otology, Rhinology & Laryngology 124, n.º 1_suppl (18 de marzo de 2015): 184S—192S. http://dx.doi.org/10.1177/0003489415575041.
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Objectives: We present 3 patients with congenital sensorineural hearing loss (SNHL) caused by novel PTPRQ mutations, including clinical manifestations and phenotypic features. Methods: Two hundred twenty (220) Japanese subjects with SNHL from unrelated and nonconsanguineous families were enrolled in the study. Targeted genomic enrichment with massively parallel DNA sequencing of all known nonsyndromic hearing loss genes was performed to identify the genetic cause of hearing loss. Results: Four novel causative PTPRQ mutations were identified in 3 cases. Case 1 had progressive profound SNHL with a homozygous nonsense mutation. Case 2 had nonprogressive profound SNHL with a compound heterozygous mutation (nonsense and missense mutation). Case 3 had nonprogressive moderate SNHL with a compound heterozygous mutation (missense and splice site mutation). Caloric test and vestibular evoked myogenic potential (VEMP) test showed vestibular dysfunction in Case 1. Conclusion: Hearing loss levels and progression among the present cases were varied, and there seem to be no obvious correlations between genotypes and the phenotypic features of their hearing loss. The PTPRQ mutations appeared to be responsible for vestibular dysfunction.