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Artykuły w czasopismach na temat "Missense mutations"
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Captur, Gabriella, Eloisa Arbustini, Petros Syrris, Dina Radenkovic, Ben O'Brien, William J. Mckenna i James C. Moon. "Lamin mutation location predicts cardiac phenotype severity: combined analysis of the published literature". Open Heart 5, nr 2 (październik 2018): e000915. http://dx.doi.org/10.1136/openhrt-2018-000915.
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ObjectiveTwo LMNA genotype–phenotype cardiac correlations are reported: first, that cardiac involvement in multisystem laminopathies prevails with mutations upstream of the nuclear localisation signal (NLS); second, that worse outcomes occur with non-missense (compared with missense) mutations. We tested whether LMNA mutation DNA location and mutation subtype can predict phenotype severity in patients with lamin heart disease.MethodsWe used a semantic workflow platform and manual electronic literature search to identify published LMNA mutations with cardiac-predominant phenotype. Hierarchical cluster analysis (HCA) assembled lamin heart disease into classes based on phenotype severity. 176 reported causative mutations were classified and any relationships to mutation location/subtype assessed by contingency analysis.ResultsMore adverse phenotype was associated with mutation location upstream of the NLS (p=0.014, OR 2.38, 95% CI 1.19 to 4.80) but not with non-missense mutations (p=0.337, OR 1.36, 95% CI 0.72 to 2.57), although an association with non-missense mutations was identified in a subcluster with malignant ventricular arrhythmia (p=0.005, OR 2.64, 95% CI 0.76 to 9.21). HCA limited to the 65 mutations described on ClinVar as pathogenic/likely pathogenic showed similar findings (upstream of NLS, p=0.030, OR 4.78, 95% CI 1.28 to 17.83; non-missense, p=0.121, OR 2.64, 95% CI 0.76 to 9.21) as did analysis limited to pathogenic/likely pathogenic variants according to the American College of Medical Genetics and Genomics standards.ConclusionCardiac patients with an LMNA mutation located upstream versus downstream of the NLS have a more adverse cardiac phenotype, and some missense mutations can be as harmful as non-missense ones.
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Caspi, Michal, Frédéric M. Coquelle, Cynthia Koifman, Talia Levy, Hiroyuki Arai, Junken Aoki, Jan R. De Mey i Orly Reiner. "LIS1 Missense Mutations". Journal of Biological Chemistry 278, nr 40 (28.07.2003): 38740–48. http://dx.doi.org/10.1074/jbc.m301147200.
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Prophet, Malshundria, Kun Xiao, Theodore Stewart Gourdin, Rebecca J. Nagy, Lesli Ann Kiedrowski, Elisa Ledet, Guru Sonpavde, A. Oliver Sartor i Michael B. Lilly. "Detection of actionable BRAF missense mutations by ctDNA-based genomic analysis in prostate cancer." Journal of Clinical Oncology 36, nr 6_suppl (20.02.2018): 306. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.306.
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306 Background: Activating BRAF fusion proteins are rare in prostate cancer (PCa) patients. Driver missense BRAF mutations have not been reported in detail in this population. Methods: We examined ctDNA-derived genomic profiles (Guardant 360) from 2,721 unique PCa patients, to identify BRAF genomic anomalies (SNVs, amplification). The ctDNA results were compared with PCa tissue-based genomics from the TCGA database (1,851 unique patients). Results: BRAF missense mutations were found in 76 ctDNA patients (2.8%) and were from all known mutation classes (I, II, III) as well as variants of unknown significance (VUSs). Only 4 patients had the V600E mutation. Multiple examples of known, autonomously active, non-canonical mutations were found (27), including K601E (12), G469A (5), D594G (2), and G466E (2). There were 45 VUSs. Mutations were primarily clonal but subclonal mutations were also found. In addition BRAF was commonly amplified, usually in the presence of multiple other amplified genes. BRAF missense mutations were more common with ctDNA than TCGA (2.8% vs 1.4%). Neither dataset identified frequent V600E mutations (ctDNA: 4/2,721; TCGA 1/1,851). However patients with the same non-canonical BRAF mutations were found in each dataset (K601E, G469A, G466E, D594G). Each dataset contained unique mutations found in only one patient. BRAF mutations potentially treatable with BRAF or MEK inhibitors (class I, II) were about half of all mutations (ctDNA 40.8%; TCGA 50%). We treated a PCa patient with a clonal BRAF(G469A) mutation with targeted therapy. The patient was resistant to multiple lines of hormonal and cytotoxic therapy. Trametinib produced a clinical and RECIST response. Conclusions: ctDNA-based genomic analysis identified multiple BRAF amplifications and missense SNVs in PCa patients. SNVs are largely non-canonical, but include known activating mutations that could act as drivers. The analysis also identified more BRAF missense mutations than did tissue genomic profiling, but the mutational landscape, overall frequency of mutations was similar with either method. ctDNA-based genomic profiling can identify actionable BRAF driver mutations that may respond to MEK and BRAF inhibitors.
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Zhang, Edward D., Meixia Zhang, Gen Li, Charlotte L. Zhang, Zhihuan Li, Guangxi Zang, Zhiguang Su i in. "Mutation spectrum in GNAQ and GNA11 in Chinese uveal melanoma". Precision Clinical Medicine 2, nr 4 (13.11.2019): 213–20. http://dx.doi.org/10.1093/pcmedi/pbz021.
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Abstract Uveal melanoma is the most common intraocular cancer in the adult eye. R183 and Q209 were found to be mutational hotspots in exon 4 and exon 5 of GNAQ and GNA11 in Caucasians. However, only a few studies have reported somatic mutations in GNAQ or GNA11 in uveal melanoma in Chinese. We extracted somatic DNA from paraffin-embedded biopsies of 63 Chinese uveal melanoma samples and sequenced the entire coding regions of exons 4 and 5 in GNAQ and GNA11. The results showed that 33% of Chinese uveal melanoma samples carried Q209 mutations while none had R183 mutation in GNAQ or GNA11. In addition, seven novel missense somatic mutations in GNAQ (Y192C, F194L, P170S, D236N, L232F, V230A, and M227I) and four novel missense somatic mutations in GNA11 (R166C, I200T, S225F, and V206M) were found in our study. The high mutation frequency of Q209 and the novel missense mutations detected in this study suggest that GNAQ and GNA11 are common targets for somatic mutations in Chinese uveal melanoma.
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Kim, Soo-Hyun, Soo Young Choi, Sung-Eun Lee, Yun Jeong Oh, Jin-Eok Park, Hae Lyun Yoo, Hye-Rim Jeon, Eun-Jung Jang i Dong-Wook Kim. "Kinetics Of Low-Level Mutant Clones Detected By Subcloning and Sequencing In Tyrosine Kinase Inhibitor Resistant CML". Blood 122, nr 21 (15.11.2013): 2720. http://dx.doi.org/10.1182/blood.v122.21.2720.2720.
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Abstract Background BCR-ABL1 kinase domain (KD) point mutation causes resistance to tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML) patients through impaired binding of TKI to the target site. Recent studies have reported that multiple mutations detected in 2-9% of patients with imatinib (IM)-resistant CML were associated with poor response rate and survival outcomes. However, biological characteristics and dynamics of multiple low-level mutations are still not assessed with a quantitative serial follow-up data in the same populations. Aims The aim of this study was to investigate biological characteristics and dynamics of low-level mutations in the serial samples from the patients carrying multiple mutations using subcloning and sequencing. Methods Since 2002, 414 CML patients were screened for mutation analysis due to sign of resistance to TKIs including imatinib (IM), nilotinib (NIL), dasatinib (DAS), bosutinib (BOS), radotinib (RAD) or ponatinib (PON) at Seoul St Mary’s Hospital using direct sequencing and allele specific oligonucleotide-polymerase chain reaction (ASO-PCR). Among them, 31 patients carried ≥ 2 BCR-ABL1 kinase domain mutations. We analyzed 137 samples from these 31 patients using subcloning and sequencing (in total, 2737 colonies were sequenced). By cloning and sequencing, two or more missense mutations present in the same clone were defined as compound mutation and co-existence of single missense mutations in the separated clones was defined as polyclonal mutation. Co-existence of single missense mutation and compound mutation harboring two or more missense mutations in the same clone was defined as mixed mutation. Missense mutations detected by direct sequencing are defined as predominant mutations. Missense mutations detected by cloning and sequencing but not by direct sequencing are defined as low-level mutations. Results In a total of 2737 colonies from 137 samples, 1596 (58%) colonies harbored ≥ 2 missense mutations with a median 2 (range, 2 – 7) mutations, and 905 (33%) colonies with a single mutation and 236 (9%) colonies with wild type were observed. In 2737 colonies, 692 different low-level mutations were detected by cloning and sequencing but not by direct sequencing. Among them, M244V, G250E, Y253H, E279K, T315I, F317L, M351T, E355A, F359I, and F359V were detected by direct sequencing in the followed-up samples, and the others remain undetectable by direct sequencing. To address whether these low-level mutations were distinct in the patients with TKI resistance, we applied the cloning and sequencing to samples from 3 healthy controls and 3 patients with optimal response to IM. 38 different mutations were detected healthy controls. 52 different mutations were detected in optimal responders. S349P, N374S, E450G, and S485P were detected in both healthy controls and optimal responders. All mutations detected in optimal responders except 3 missense mutations (V335A, F382V, and A395S) were detected as low-level mutations in the 31 patients’ cohort with TKI resistance. Of 38 different mutations detected in healthy control, 31 mutations except 7 missense mutations (Y264H, M343R, A350V, E373G, G298R, E462K, and T495K) were also detected as low-level mutations in the 31 patients’ cohort. Conclusions We showed basic characteristics and dynamics of low-level mutations by subcloning and sequencing. Some of the low-level mutant clones harboring previously known (clinically common) TKI resistant mutations changes to the predominant in the followed-up samples. Except them, most low-level mutant clones were not detected repeatly and did not increase gradually in the serial samples, implying that they may not have clinical significance. Disclosures: No relevant conflicts of interest to declare.
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Boettcher, Steffen, Peter G. Miller, Rohan Sharma, Marie McConkey, Matthew Leventhal, Andrei V. Krivtsov, Andrew O. Giacomelli i in. "A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies". Science 365, nr 6453 (8.08.2019): 599–604. http://dx.doi.org/10.1126/science.aax3649.
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TP53, which encodes the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, are enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We used CRISPR-Cas9 to generate isogenic human leukemia cell lines of the most common TP53 missense mutations. Functional, DNA-binding, and transcriptional analyses revealed loss of function but no GOF effects. Comprehensive mutational scanning of p53 single–amino acid variants demonstrated that missense variants in the DNA-binding domain exert a dominant-negative effect (DNE). In mice, the DNE of p53 missense variants confers a selective advantage to hematopoietic cells on DNA damage. Analysis of clinical outcomes in patients with acute myeloid leukemia showed no evidence of GOF for TP53 missense mutations. Thus, a DNE is the primary unit of selection for TP53 missense mutations in myeloid malignancies.
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Shih, Lee-Yung, Der-Cherng Liang, Chein-Fuang Huang, Ming-Chung Kuo, Tung-Liang Lin, Jen-Fen Fu, Yu-Shu Shih i in. "Different Patterns of AML1 Mutations between De Novo Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia." Blood 110, nr 11 (16.11.2007): 2442. http://dx.doi.org/10.1182/blood.v110.11.2442.2442.
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Abstract Background: Transcription factor AML1/RUNX1 is essential for normal hematopoiesis. AML1 mutations have been described in radiation-associated and therapy-related myelodysplastic syndrome (MDS) and have rarely been reported in patients with chronic myelomonocytic leukemia (CMML). Aims: We sought (1) to define the frequencies of AML1 mutations in de novo MDS and CMML, and (2) to compare the difference in mutation patterns between the two disorders. Methods: AML1 mutations were examined on bone marrow samples obtained at initial diagnosis from 107 patients with de novo MDS (12 RCMD, 45 RAEB1 and 50 RAEB2) and 79 patients with CMML (53 CMML1 and 26 CMML2). Mutational analysis was performed by direct sequencing of all RT-PCR products amplified with 3 overlapping primer pairs which cover the entire coding sequences of AML1b gene from exon 1 through exon 8. Samples with abnormal sequencing results were subjected to repeated PCR and sequencing using genomic DNA with alternative primers. Results: Seventeen of 107 patients with MDS (15.9%) had 20 AML1 mutations; 8 mutations were located in Runt homology domain (RHD) (exons 3–5) and 12 mutations were located in the non-RHD region (exons 6–8). The 20 AML1 mutations included 9 missense mutations, 5 nonsense mutations, 2 frameshift mutations, and 4 silent mutations. One patient has two missense mutations at RHD and another two had one missense mutation with one silent mutation. Thirty-one AML1 mutations were detected in 29 of 79 CMML patients (36.7%); 20 patients had 22 mutations located in the N-terminal part and the remaining 9 patients had one single mutation located in the C-terminal region. The patterns of the 31 mutations consisted of 8 missense mutations, 7 nonsense mutations, 15 frameshift mutations and 1 silent mutation. One CMML patient had two missense mutations in RHD and another patient had two frameshift mutations in RHD. Cloning analysis showed that the two mutations were on different alleles in both patients. The frequency of AML1 mutations was significantly higher in patients with CMML than in MDS (P=0.002). Mutations in N-terminal region occurred more frequently in CMML than in MDS (22/30 vs. 8/20, P=0.042). CMML patients had a higher frequency of frameshift mutations as compared with MDS patients (P=0.006). Except for a significantly lower platelet count in CMML patients with AML1 mutations, there were no differences in age, sex, blood counts, percentages of blasts in bone marrow or peripheral blood, subtypes of MDS or CMML, cytogenetic risk groups, time to AML transformation or overall survival between AML1(+) and AML1(−) in MDS and between AML1(+) and AML1(−) CMML patients. Conclusion: Our results showed that AML1 mutations occurred frequently in both de novo MDS and CMML but with different mutation patterns.
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Zabransky, Daniel J., Christopher L. Yankaskas, Rory L. Cochran, Hong Yuen Wong, Sarah Croessmann, David Chu, Shyam M. Kavuri i in. "HER2 missense mutations have distinct effects on oncogenic signaling and migration". Proceedings of the National Academy of Sciences 112, nr 45 (27.10.2015): 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 i Emil Alexov. "Analyzing Effects of Naturally Occurring Missense Mutations". Computational and Mathematical Methods in Medicine 2012 (2012): 1–15. http://dx.doi.org/10.1155/2012/805827.
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Single-point mutation in genome, for example, single-nucleotide polymorphism (SNP) or rare genetic mutation, is the change of a single nucleotide for another in the genome sequence. Some of them will produce an amino acid substitution in the corresponding protein sequence (missense mutations); others will not. This paper focuses on genetic mutations resulting in a change in the amino acid sequence of the corresponding protein and how to assess their effects on protein wild-type characteristics. The existing methods and approaches for predicting the effects of mutation on protein stability, structure, and dynamics are outlined and discussed with respect to their underlying principles. Available resources, either as stand-alone applications or webservers, are pointed out as well. It is emphasized that understanding the molecular mechanisms behind these effects due to these missense mutations is of critical importance for detecting disease-causing mutations. The paper provides several examples of the application of 3D structure-based methods to model the effects of protein stability and protein-protein interactions caused by missense mutations as well.
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Vierimaa, O., T. M. L. Ebeling, S. Kytölä, R. Bloigu, E. Eloranta, J. Salmi, E. Korpi-Hyövälti i in. "Multiple endocrine neoplasia type 1 in Northern Finland; clinical features and genotype–phenotype correlation". European Journal of Endocrinology 157, nr 3 (wrzesień 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.
Rozprawy doktorskie na temat "Missense mutations"
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Ibrahim, Daniel Murad. "ChIP-seq reveals mutation-specific pathomechanisms of HOXD13 missense mutations". Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2015. http://dx.doi.org/10.18452/17102.
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Mutationen von Transkriptionsfaktoren (TF) betreffen nicht nur die Funktion des TFs, sondern auch die Expression seiner Zielgene und liegen häufig angeborenen Entwicklungsdefekten zugrunde. Über 20 Mutationen in HOXD13, einem TF der die Entwicklung der Extremitäten kontrolliert, sind bisher als Ursache verschiedenartiger Extremitätenfehlbildungen entdeckt worden. Eine molekularbiologische Grundlage für die Vielgestaltigkeit der HOXD13-Mutationen ist jedoch unbekannt. Die bisherigen Methoden zur funktionellen Charakterisierung von TF-Mutationen ermöglichten eine lediglich eingeschränkte Interpretation der molekularen Pathomechanismen. Die kürzlich entwickelte ChIP-seq Methode ermöglicht eine umfassende, funktionelle Charakterisierung eines TFs. In dieser Arbeit wurde eine Methode etabliert, um eine Vielzahl von Transkriptionsfaktoren und TF-Mutationen systematisch zu untersuchen. Zur Validierung wurden zwei neue Punktmutationen in HOXD13, p.Q317K und p.R298Q, charakterisiert. Beide Mutationen betreffen die DNA-bindende Domäne von HOXD13, rufen aber stark unterschiedliche Fehlbildungen hervor. Die Ergebnisse zeigen, dass die HOXD13Q317K Mutante eine veränderte Sequenzspezifität aufweist, welche nun jener eines anderen TFs, PITX1, ähnelt. Auch genomweit zeigt HOXD13Q317K ein Bindungsprofil, welches eher PITX1 als HOXD13wt entspricht. Durch weitere, unabhängige Analysen und Experimente wurde bestätigt, dass die p.Q317K Mutation HOXD13 in einen TF mit PITX1-ähnlichen Eigenschaften verändert. Die HOXD13R298Q-Mutante zeigt eine weitgehend unveränderte Bindungssequenz gegenüber HOXD13wt, jedoch eine veränderte Zusammensetzung der genomischen Bindestellen. Dies weist, in Kombination mit dem humanen Phänotyp auf einen dominant-negativen Pathomechanismus dieser Mutanten hin. Zusammengenommen zeigt diese Arbeit durch die Erhebung von experimentellen Daten, dass klar unterscheidbare molekularbiologische Mechanismen den HOXD13Q317K- und HOXD13R298Q-Mutationen zugrunde liegen.Mutations in transcription factors (TF) do not only affect the function of the TF, but also the expression of its target genes and are frequently underlying congenital malformations. More than 20 distinct pathogenic mutations in HOXD13, a TF controlling limb development, have been associated with a broad range of limb malformations. However, a molecular basis underlying the variability of HOXD13-associated phenotypes remains elusive. To date, the experimental methods used to functionally characters TF mutations have allowed only limited insights into the underlying molecular pathomechanisms. The recently developed ChIP-seq technology has proven to be a powerful method to profile the binding characteristics of TFs; however a number of technical hurdles hinder its application for functional characterization of mutant TFs. This work describes the establishment of a ChIP-seq approach to investigate a wide spectrum of TFs and TF mutations. The approach was applied to characterize two previously unknown missense mutations in HOXD13, p.Q317K and p.R298Q, which both alter the DNA-binding domain of HOXD13 but cause very different disease phenotypes. The results show that the HOXD13Q317K mutant has an altered sequence specificity that resembles the recognition sequence of another TF, PITX1. Further, the genome-wide binding pattern of HOXD13Q317K shifts towards a more PITX1-like binding pattern. Even further analysis and viral overexpression in chicken limb buds confirm that the mutation partially converts HOXD13Q317K into a TF with PITX1-like properties. The HOXD13R298Q has a largely unchanged sequence specificity, but an altered composition of genomic binding sites. This, in combination with the human phenotype, indicates that the mutant might act in a dominant-negative manner. Collectively, this work shows through generation of direct experimental evidence, that clearly distinct molecular mechanisms underlie the pathogenicity of HOXD13Q317K and HOXD13R298Q mutations.
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Zerey, Marc. "Functional analysis of human MLH1 missense mutations using Saccharomyces cerevisiae". Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=79210.
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Hereditary nonpolyposis colorectal carcinoma (HNPCC) is linked to inherited defects in human genes (hMLH1, hMSH2, hMSH6, hPMS1, and hPMS2) that are involved in the repair of mismatched bases that may occur during DNA replication. Germline missense mutations in human MLH1 (hMLH1) are frequently detected and their functional characterization is critical to the development of genetic testing for HNPCC. We used several functional assays to characterize two hMLH1 mutations: T117M and R182G. Saccharomyces cerevisiae were transformed with hMLH1 cDNA expression vectors containing either mutation. The presence of functional hMLH1 produces an accumulation of mutations in mismatch repair (MSM)-proficient yeast due to MLH1 protein homology and interference with normal MMR. The transformants were tested for increased mutation rates using three assays: mutation of the gene for canavanine resistance (CAN1 ), reversion of the hom 3--10 allele, and insertion-deletions at a dinucleotide repeat regulating expression of beta-galactosidase. Based on the results of these assays T117M is likely a functional mutation while R182G may be a polymorphism. We conclude that this assay may be applicable in genetic testing for HNPCC.
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Maxwell, Megan Amanda, i n/a. "PEX1 Mutations in Australasian Patients with Disorders of Peroxisome Biogenesis". Griffith University. School of Biomolecular and Biomedical Science, 2004. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20040219.100649.
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The peroxisome is a subcellular organelle that carries out a diverse range of metabolic functions, including the b-oxidation of very long chain fatty acids, the breakdown of peroxide and the a-oxidation of fatty acids. Disruption of peroxisome metabolic functions leads to severe disease in humans. These diseases can be broadly grouped into two categories: those in which a single enzyme is defective, and those known as the peroxisome biogenesis disorders (PBDs), which result from a generalised failure to import peroxisomal matrix proteins (and consequently result in disruption of multiple metabolic pathways). The PBDs result from mutations in PEX genes, which encode protein products called peroxins, required for the normal biogenesis of the peroxisome. PEX1 encodes an AAA ATPase that is essential for peroxisome biogenesis, and mutations in PEX1 are the most common cause of PBDs worldwide. This study focused on the identification of mutations in PEX1 in an Australasian cohort of PBD patients, and the impact of these mutations on PEX1 function. As a result of the studies presented in this thesis, twelve mutations in PEX1 were identified in the Australasian cohort of patients. The identified mutations can be broadly grouped into three categories: missense mutations, mutations directly introducing a premature termination codon (PTC) and mutations that interrupt the reading frame of PEX1. The missense mutations that were identified were R798G, G843D, I989T and R998Q; all of these mutations affect amino acid residues located in the AAA domains of the PEX1 protein. Two mutations that directly introduce PTCs into the PEX1 transcript (R790X and R998X), and four frameshift mutations (A302fs, I370fs, I700fs and S797fs) were identified. There was also one mutation found in an intronic region (IVS22-19A>G) that is presumed to affect splicing of the PEX1 mRNA. Three of these mutations, G843D, I700fs and G973fs, were found at high frequency in this patient cohort. At the commencement of these studies, it was hypothesised that missense mutations would result in attenuation of PEX1 function, but mutations that introduced PTCs, either directly or indirectly, would have a deleterious effect on PEX1 function. Mutations introducing PTCs are thought to cause mRNA to be degraded by the nonsense-mediated decay of mRNA (NMD) pathway, and thus result in a decrease in PEX1 protein levels. The studies on the cellular impact of the identified PEX1 mutations were consistent with these hypotheses. Missense mutations were found to reduce peroxisomal protein import and PEX1 protein levels, but a residual level of function remained. PTC-generating mutations were found to have a major impact on PEX1 function, with PEX1 mRNA and protein levels being drastically reduced, and peroxisomal protein import capability abolished. Patients with two missense mutations showed the least impact on PEX1 function, patients with two PTC-generating mutations had a severe defect in PEX1 function, and patients carrying a combination of a missense mutation and a PTC-generating mutation showed levels of PEX1 function that were intermediate between these extremes. Thus, a correlation between PEX1 genotype and phenotype was defined for the Australasian cohort of patients investigated in these studies. For a number of patients, mutations in the coding sequence of one PEX1 allele could not be identified. Analysis of the 5' UTR of this gene was therefore pursued for potential novel mutations. The initial analyses demonstrated that the 5' end of PEX1 extended further than previously reported. Two co-segregating polymorphisms were also identified, termed 137 T>C and 53C>G. The -137T>C polymorphism resided in an upstream, in-frame ATG (termed ATG1), and the possibility that the additional sequence represented PEX1 coding sequence was examined. While both ATGs were found to be functional by virtue of in vitro and in vivo expression investigations, Western blot analysis of the PEX1 protein in patient and control cell extracts indicated that physiological translation of PEX1 was from the second ATG only. Using a luciferase reporter approach, the additional sequence was found to exhibit promoter activity. When examined alone the -137T>C polymorphism exerted a detrimental effect on PEX1 promoter activity, reducing activity to half that of wild-type levels, and the -53C>G polymorphism increased PEX1 promoter activity by 25%. When co-expressed (mimicking the physiological condition) these polymorphisms compensated for each other to bring PEX1 promoter activity to near wild-type levels. The PEX1 mutations identified in this study have been utilised by collaborators at the National Referral Laboratory for Lysosomal, Peroxisomal and Related Genetic Disorders (based at the Women's and Children's Hospital, Adelaide), in prenatal diagnosis of the PBDs. In addition, the identification of three common mutations in Australasian PBD patients has led to the implementation of screening for these mutations in newly referred patients, often enabling a precise diagnosis of a PBD to be made. Finally, the strong correlation between genotype and phenotype for the patient cohort investigated as part of these studies has generated a basis for the assessment of newly identified mutations in PEX1.
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Maxwell, Megan Amanda. "PEX1 Mutations in Australasian Patients with Disorders of Peroxisome Biogenesis". Thesis, Griffith University, 2004. http://hdl.handle.net/10072/366184.
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The peroxisome is a subcellular organelle that carries out a diverse range of metabolic functions, including the b-oxidation of very long chain fatty acids, the breakdown of peroxide and the a-oxidation of fatty acids. Disruption of peroxisome metabolic functions leads to severe disease in humans. These diseases can be broadly grouped into two categories: those in which a single enzyme is defective, and those known as the peroxisome biogenesis disorders (PBDs), which result from a generalised failure to import peroxisomal matrix proteins (and consequently result in disruption of multiple metabolic pathways). The PBDs result from mutations in PEX genes, which encode protein products called peroxins, required for the normal biogenesis of the peroxisome. PEX1 encodes an AAA ATPase that is essential for peroxisome biogenesis, and mutations in PEX1 are the most common cause of PBDs worldwide. This study focused on the identification of mutations in PEX1 in an Australasian cohort of PBD patients, and the impact of these mutations on PEX1 function. As a result of the studies presented in this thesis, twelve mutations in PEX1 were identified in the Australasian cohort of patients. The identified mutations can be broadly grouped into three categories: missense mutations, mutations directly introducing a premature termination codon (PTC) and mutations that interrupt the reading frame of PEX1. The missense mutations that were identified were R798G, G843D, I989T and R998Q; all of these mutations affect amino acid residues located in the AAA domains of the PEX1 protein. Two mutations that directly introduce PTCs into the PEX1 transcript (R790X and R998X), and four frameshift mutations (A302fs, I370fs, I700fs and S797fs) were identified. There was also one mutation found in an intronic region (IVS22-19A>G) that is presumed to affect splicing of the PEX1 mRNA. Three of these mutations, G843D, I700fs and G973fs, were found at high frequency in this patient cohort. At the commencement of these studies, it was hypothesised that missense mutations would result in attenuation of PEX1 function, but mutations that introduced PTCs, either directly or indirectly, would have a deleterious effect on PEX1 function. Mutations introducing PTCs are thought to cause mRNA to be degraded by the nonsense-mediated decay of mRNA (NMD) pathway, and thus result in a decrease in PEX1 protein levels. The studies on the cellular impact of the identified PEX1 mutations were consistent with these hypotheses. Missense mutations were found to reduce peroxisomal protein import and PEX1 protein levels, but a residual level of function remained. PTC-generating mutations were found to have a major impact on PEX1 function, with PEX1 mRNA and protein levels being drastically reduced, and peroxisomal protein import capability abolished. Patients with two missense mutations showed the least impact on PEX1 function, patients with two PTC-generating mutations had a severe defect in PEX1 function, and patients carrying a combination of a missense mutation and a PTC-generating mutation showed levels of PEX1 function that were intermediate between these extremes. Thus, a correlation between PEX1 genotype and phenotype was defined for the Australasian cohort of patients investigated in these studies. For a number of patients, mutations in the coding sequence of one PEX1 allele could not be identified. Analysis of the 5' UTR of this gene was therefore pursued for potential novel mutations. The initial analyses demonstrated that the 5' end of PEX1 extended further than previously reported. Two co-segregating polymorphisms were also identified, termed –137 T>C and –53C>G. The -137T>C polymorphism resided in an upstream, in-frame ATG (termed ATG1), and the possibility that the additional sequence represented PEX1 coding sequence was examined. While both ATGs were found to be functional by virtue of in vitro and in vivo expression investigations, Western blot analysis of the PEX1 protein in patient and control cell extracts indicated that physiological translation of PEX1 was from the second ATG only. Using a luciferase reporter approach, the additional sequence was found to exhibit promoter activity. When examined alone the -137T>C polymorphism exerted a detrimental effect on PEX1 promoter activity, reducing activity to half that of wild-type levels, and the -53C>G polymorphism increased PEX1 promoter activity by 25%. When co-expressed (mimicking the physiological condition) these polymorphisms compensated for each other to bring PEX1 promoter activity to near wild-type levels. The PEX1 mutations identified in this study have been utilised by collaborators at the National Referral Laboratory for Lysosomal, Peroxisomal and Related Genetic Disorders (based at the Women's and Children's Hospital, Adelaide), in prenatal diagnosis of the PBDs. In addition, the identification of three common mutations in Australasian PBD patients has led to the implementation of screening for these mutations in newly referred patients, often enabling a precise diagnosis of a PBD to be made. Finally, the strong correlation between genotype and phenotype for the patient cohort investigated as part of these studies has generated a basis for the assessment of newly identified mutations in PEX1.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Biomedical Sciences
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岡田, 浩美, H. Okada, T. Yamazaki, A. Takagi, T. Murate, K. Yamamoto, J. Takamatsu i in. "In vitro characterization of missense mutations associated with quantitative protein Sdeficiency". Thesis, Schattauer, 2006. http://hdl.handle.net/2237/11695.
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名古屋大学博士学位論文 学位の種類:博士（医療技術学）（課程）学位授与年月日:平成19年3月23日"In vitro characterization of missense mutations associated with quantitative protein Sdeficiency" Schattauer, v.4, iss.9, pp.2003-2009を、博士論文として提出したもの。
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Drozdova, Tetyana. "Nephrin missense mutations altez cellular trafficking and induce endoplasmic retioulum stress". Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=106541.
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Nephrin, a key component of the filtration slit diaphragm, undergoes post-translational modifications in the endoplasmic reticulum (ER). Mutations in nephrin lead to proteinuria. We examined the effects of missense mutations in nephrin on protein folding in the ER, cellular trafficking, and induction of the unfolded protein response (UPR). Wild type (WT) nephrin and the I171N, G270C, S366R, S724C and R743C mutant cDNAs were expressed in 293T cells or glomerular epithelial cells (GECs) by transient transfection. Association of nephrin with the ER chaperone, calnexin, was studied by co-immunoprecipitation. Activation of the UPR was assessed by monitoring expression of the ER chaperone, Grp94, phosphorylation of eukaryotic translation initiation factor-2α subunit (eIF2α), and induction of C/EBP homologous protein-10 (CHOP), as well as activating transcription factor-6 (ATF6)-luciferase reporter activity. All nephrin mutants showed increased association with calnexin, compared with WT nephrin. The I171N and G270C mutants increased expression of Grp94 in 293T cells, and stimulated ATF6-luciferase activity in both 293T cells and GECs. Nephrin S366R and S724C tended to induce the UPR, but changes in Grp94 and ATF6-luciferase activity were less consistent. The R743C mutant did not enhance Grp94 expression, nor ATF6-luciferase activity. All nephrin mutants did not increase eIF2α phosphorylation, nor CHOP expression. Immunofluorescence microscopy showed WT nephrin at the plasma membrane, while the I171N and S366R mutants were perinuclear, colocalized with calnexin. Moreover, the two nephrin mutants induced aggregation of the ER chaperone, calreticulin, compared with WT. Treatment of cells with castanospermine (which reduces the interaction of nephrin with calnexin) resulted in a portion of nephrin I171N and S366R appearing at the plasma membrane. Thus, certain nephrin mutants show impaired folding in the ER, and activate the ATF6 branch of the UPR. Induction of ER chaperones may represent a cytoprotective response, allowing cells to withstand proteotoxic injury. Blocking the interaction of nephrin with calnexin results in a partial rescue of certain nephrin mutants to the plasma membrane.La néphrine, un composant clé du diaphragme de fente, subit des modifications post-traductionnelles dans le réticulum endoplasmique (RE). Des mutations de la néphrine provoquent une protéinurie. Nous avons examiné les effets des mutations faux-sens de la néphrine sur le repliement de cette protéine dans RE, sur son trafic cellulaire et sur l'induction de réponse déplié protéines (UPR). Le type sauvage (TS) de la néphrine et les mutants d'ADNc, I171N, G270C, S366R, S724C et R743C ont été exprimés dans des cellules 293T ou cellules glomérulaires épithéliales (GECs) par une transfection transitoire. Association de néphrine avec le chaperon de RE, la calnexine, a été étudiée par la co-immunoprécipitation. Activation de l'UPR a été évaluée par l'étude de l'expression du chaperon du RE, Grp94, la phosphorylation de la sous-unité (eIF2α) du facteur 2α d'initiation de la traduction eucaryote, et l'induction de C/EBP homologue de la protéine-10 (CHOP), ainsi que l'activation du facteur-6 de la transcription (ATF6)- l'activité luciférase du gène rapporteur. Tous les mutants de la néphrine ont montré l'association accrue avec la calnexine, par rapport au TS de la néphrine. Les mutants I171N et le G270C ont augmenté l'expression du Grp94 dans les cellules 293T, ont stimulé l'ATF6-activité luciférase dans les deux cellules 293T et GECs. Néphrine S366R et S724C ont tendance à induire l'UPR, mais les changements dans le Grp94 et l'activité ATF6-luciférase ont été moins cohérents. Le mutant R743C n'a pas amélioré l'expression de Grp94, ni l'ATF6-activité luciférase. Tous les mutants de la néphrine n'ont pas augmenté ni la phosphorylation d'eIF2α, ni l'expression de CHOP. La microscopie en immunofluorescence a montré la localisation du TS néphrine à la membrane plasmique, tandis que les mutants I171N et S366R à la partie périnucléaire, colocalisés avec la calnexine. Par ailleurs, les deux mutants de néphrine ont provoqué l'agrégation du chaperon du RE, la calréticuline, par rapport au TS. Le traitement des cellules avec la castanospermine (qui réduit l'interaction de la néphrine avec la calnexine) a entraîné la localisation d'une partie des mutants I171N et S366R de la néphrine à la membrane plasmique. Ainsi, certains mutants de néphrine montrent une déficience du repliment de la protéine dans RE et activent la branche ATF6 de l'UPR. L'induction de chaperons du RE peut représenter une réponse cytoprotectrice, permettant aux cellules de résister aux lesions protéotoxique. Le blocage de l'interaction de la néphrine avec la calnexine resulte à un retour partiel au TS de certains mutants de néphrine, et donc à la localisation de néphrine à la membrane plasmique.
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Ibrahim, Daniel Murad [Verfasser], Stefan [Akademischer Betreuer] Mundlos i Petra [Akademischer Betreuer] Seemann. "ChIP-seq reveals mutation-specific pathomechanisms of HOXD13 missense mutations / Daniel Murad Ibrahim. Gutachter: Stefan Mundlos ; Petra Seemann". Berlin : Humboldt Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2015. http://d-nb.info/1065301065/34.
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Ibrahim, Daniel [Verfasser], Stefan [Akademischer Betreuer] Mundlos i Petra [Akademischer Betreuer] Seemann. "ChIP-seq reveals mutation-specific pathomechanisms of HOXD13 missense mutations / Daniel Murad Ibrahim. Gutachter: Stefan Mundlos ; Petra Seemann". Berlin : Humboldt Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2015. http://nbn-resolving.de/urn:nbn:de:kobv:11-100225655.
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Hasselbacher, Katrin. "Recessive missense mutations in LAMB2 expand the clinical spectrum of LAMB2 associated disorders /". Erlangen, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000252715.
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Sabbagh, Yves. "Impact of disease-causing missense mutations on the structure and function of PHEX". Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=38517.
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X-linked hypophosphatemia (XLH), the most prevalent form of inherited rickets in humans, is caused by mutations in the PHEX gene, which encodes a protein with high homology to the M13 family of type-II integral membrane zinc metallopeptidases. We created an online mutation database, PHEXdb (http://data.mch.mcgill.ca/phexdb), to catalogue PHEX mutations identified in XLH patients, and found that missense mutations account for 22% of the 157 mutations reported to date. We also undertook to examine the effects of eight missense mutations (C85R, D237G, Y317F, G579R, G579V, S711R, A720T, and F731Y) on synthesis, glycosylation, cellular trafficking, and catalytic activity of the recombinant proteins using several approaches. The wild-type protein was resistant to endoglycosidase H (endo H), indicating that it is fully glycosylated. In addition, biotinylation and immunofluorescence studies revealed that the wild-type protein resides at the cell surface. The D237G, Y317F and F731Y mutant PHEX proteins were also endo H resistant and thus terminally glycosylated. In contrast, endo H digestion demonstrated that C85R, G579R, G579V, S711R and A720T were not terminally glycosylated. Furthermore, immunofluorescence showed that C85R, G579R and S711R were sequestered in the endoplasmic reticulum (ER). A secreted form of wild-type and mutant PHEX (secPHEX) proteins was generated to examine catalytic activity, using a synthetic fluorogenic peptide substrate. For this purpose, rescue of ER-trapped mutant proteins was attempted by growing transfected cells at 26°C. Low temperature was able to rescue three of the five trapped mutant proteins (G579V, S711R and A720T). Residual catalytic activity was observed with four mutant proteins (D237G, Y317F, A720T and F731Y) relative to the wild-type. However, the rescued S711R mutant was devoid of catalytic activity. Finally, limited proteolysis with trypsin and endoproteinase Glu-c revealed that the mutations D237G and F731Y induce conform
Książki na temat "Missense mutations"
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Bergmann, Carsten, i Klaus Zerres. Autosomal recessive polycystic kidney disease. Redaktor Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0313.
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Autosomal recessive polycystic kidney disease (ARPKD) is an important cause of childhood renal- and liver-related morbidity and mortality with variable disease expression. Many patients manifest peri- or neonatally with a mortality rate of 30–50%, whereas others survive to adulthood with only minor clinical features. ARPKD is typically caused by mutations in the PKHD1 gene that encodes a 4074-amino acid type 1 single-pass transmembrane protein called fibrocystin or polyductin. Fibrocystin/polyductin is among other cystoproteins expressed in primary cilia, basal bodies, and centrosomes, but its exact function has still not been fully unravelled. Mutations were found to be scattered throughout the gene with many of them being private to single families. Correlations have been drawn for the type of mutation rather than for the site of the individual mutation. Virtually all patients carrying two truncating mutations display a severe phenotype with peri- or neonatal demise while surviving patients bear at least one hypomorphic missense mutation. However, about 20–30% of all sibships exhibit major intrafamilial phenotypic variability and it becomes increasingly obvious that ARPKD is clinically and genetically much more heterogeneous and complex than previously thought.
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Burghes, Arthur H. M., i Vicki L. McGovern. Spinal Muscular Atrophy. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0034.
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Spinal muscular atrophies affect the lower motor neuron. The most common SMA maps to 5q is an autosomal recessive disorder. SMA is caused by loss or mutation of the SMN1 gene and retention of the SMN2 gene, and these genes lie in a complex area of the genome. Mild missense alleles of SMN1 work to complement SMN2 to give function and therapeutics that restore SMN levels are in clinical testing. Modifiers that lie outside the SMN gene locus and influence severity clearly exist, but what they are remains unknown as do the critical genes affected by SMN deficiency.
Części książek na temat "Missense mutations"
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Guziewicz, Karina E., Gustavo D. Aguirre i Barbara Zangerl. "Modeling the Structural Consequences of BEST1 Missense Mutations". W Retinal Degenerative Diseases, 611–18. Boston, MA: Springer US, 2011. http://dx.doi.org/10.1007/978-1-4614-0631-0_78.
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Sun, Haiyang, Zhenyu Yue, Le Zhao, Junfeng Xia, Yannan Bin i Di Zhang. "Computational Prediction of Driver Missense Mutations in Melanoma". W Intelligent Computing Theories and Application, 438–47. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-95933-7_53.
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Sahara, Naruhiko, Takami Tomiyama i Hiroshi Mori. "Rearrangement of microtubule networks by tau bearing missense mutations". W Neuroscientific Basis of Dementia, 113–20. Basel: Birkhäuser Basel, 2001. http://dx.doi.org/10.1007/978-3-0348-8225-5_13.
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Ozturk, Kivilcim, i Hannah Carter. "Identifying Driver Interfaces Enriched for Somatic Missense Mutations in Tumors". W Methods in Molecular Biology, 51–72. New York, NY: Springer New York, 2018. http://dx.doi.org/10.1007/978-1-4939-8967-6_4.
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Zhang, Xiyu, Ruoqing Xu, Yannan Bin i Zhenyu Yue. "Distinguishing Driver Missense Mutations from Benign Polymorphisms in Breast Cancer". W Intelligent Computing Theories and Application, 294–302. Cham: Springer International Publishing, 2019. http://dx.doi.org/10.1007/978-3-030-26969-2_28.
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Carter, Hannah, i Rachel Karchin. "Predicting the Functional Consequences of Somatic Missense Mutations Found in Tumors". W Gene Function Analysis, 135–59. Totowa, NJ: Humana Press, 2013. http://dx.doi.org/10.1007/978-1-62703-721-1_8.
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Thow, Graham, i Robert J. Spreitzer. "Missense Mutations in the Chloroplast rbcL Gene That Affect Rubisco Holoenzyme Assembly". W Research in Photosynthesis, 633–36. Dordrecht: Springer Netherlands, 1992. http://dx.doi.org/10.1007/978-94-009-0383-8_137.
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McLean, P. J., S. Ribich i B. T. Hyman. "Subcellular localization of α-synuclein in primary neuronal cultures: effect of missense mutations". W Advances in Research on Neurodegeneration, 53–63. Vienna: Springer Vienna, 2000. http://dx.doi.org/10.1007/978-3-7091-6284-2_5.
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Lobo, Glenn P., Lindsey A. Ebke, Adrian Au i Stephanie A. Hagstrom. "TULP1 Missense Mutations Induces the Endoplasmic Reticulum Unfolded Protein Response Stress Complex (ER-UPR)". W Retinal Degenerative Diseases, 223–30. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-17121-0_30.
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Méndez, Manuel, Barbara X. Granata, María J. Morán Jiménez, Victoria E. Parera, Alcira Batlle, Rafael Enríquez de Salamanca i María V. Rossetti. "Functional Characterization of Five Protoporphyrinogen oxidase Missense Mutations Found in Argentinean Variegate Porphyria Patients". W JIMD Reports, 91–97. Berlin, Heidelberg: Springer Berlin Heidelberg, 2011. http://dx.doi.org/10.1007/8904_2011_77.
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Lei, Xue, Boshen Wang, Alan Perez-Rathke, Wei Tian, Chia-Yi Chou, Yan-Yuan Tseng i Jie Liang. "Predicting Oncogenic Missense Mutations". W 2019 IEEE EMBS International Conference on Biomedical & Health Informatics (BHI). IEEE, 2019. http://dx.doi.org/10.1109/bhi.2019.8834553.
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Martelotto, Luciano G., Yan Zhang, Charlotte K. Y. Ng, Salvatore Piscuoglio, Jorge S. Reis-Filho i Britta Weigelt. "Abstract 4258: Benchmarking algorithms for mutation impact prediction using functionally validated missense mutations". W Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-4258.
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Lee, Peter C. W. "Abstract 3542: Missense mutations in USE1 promote lung tumorigenesis". W Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-3542.
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Kelemen, Linda E., James D. Brenton, David D. Bowtell i Brooke L. Fridley. "Abstract A14: TP53 missense mutations associate with different metabolic pathways". W Abstracts: AACR Special Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; October 1-4, 2017; Pittsburgh, PA. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1557-3265.ovca17-a14.
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Cambraia, Amanda, Mario Campos Junior, Fernanda Gubert, Juliana Ferreira Vasques, Marli Pernes da Silva Loureiro, Claudio Heitor Gress, José Mauro Bráz de Lima, Rosalia Mendez Otero i Verônica Marques Zembrzuski. "A novel mutation in the RRM2 domain of TDP-43 in a Brazilian sporadic ALS patient." W XIII Congresso Paulista de Neurologia. Zeppelini Editorial e Comunicação, 2021. http://dx.doi.org/10.5327/1516-3180.486.
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Introduction: Amyotrophic Lateral Sclerosis (ALS) is an adult-onset progressive and fatal neurodegenerative disease that selectively affects upper and lower motor neurons. Death occurs within 3 to 5 years of onset, usually from respiratory complications. Most cases of ALS are sporadic (SALS), but familial forms of the disease (FALS) represent approximately 10% of the cases. More than 30 genes have been associated with ALS and mutations in these genes account for more than a half of all familial cases and about 10% of sporadic cases. One of the most prevalent genes is TARDBP, responsible for approximately 4-6% of FALS and nearly 1-2% of SALS cases. The aim of this study was to perform the screening of known ALS genes, to increase the knowledge of the mutations that circulate in the population from Rio de Janeiro. Methods: The screening of mutations was performed through the Illumina Next Generation Sequencing (NGS) platform with the use of a sequencing panel that contained the TARDBP, SOD1, FUS, VAPB, SMN1 and SMN2 genes. Results: A novel missense mutation (p.Phe194Leu) in exon 5 of the TARDBP gene was found in a sporadic male patient who died at the age of 58 (2018). The mutation, a TTT/CTT substitution, was not detected in any mutation databases and in the literature. In silico analysis of this variant with different algorithms were performed and the results pointed to a probably damaging impact and that the mutation is disease causing. Conclusion: Through the study of the ALS genes by the NGS, we were able to identify a novel TARDBP mutation in a non-familial ALS patient. In addition, this study also increases the number of known TARDBP mutations in ALS patients and our knowledge of the mutations that affect the patients from of population from Rio de Janeiro.
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Hart, SN, T. Hoskin, H. Shimelis, B. Feng, NM Lindor, A. Monteiro, E. Iversen, DE Goldgar, V. Suman i FJ Couch. "Abstract P2-02-03: Optimized prediction of deleterious missense mutations inBRCA1andBRCA2genes". W Abstracts: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, Texas. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.sabcs16-p2-02-03.
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Antonarakis, E. "The Molecular Genetics of Hemophilia A Stylianos". W XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643980.
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Hemophilia A is a common X linked hereditary disorder of blood coagulation due to deficiency of factor 8. The gene for factor 8 has been cloned and characterized (Nature 312:326-342, 1984). It is divided into 26 exons and 25 introns and spans 186 kb of DNA. The CGNA is 9 kb and codes for 2351 amino acids. The first 19 amino acids comprise the secretory leader peptide and the mature excreted polypeptide consists of 2332 amino acids. The nucleotide sequence of the exons and the exon-intron junctions is known and the complete amino acid sequence has been deducedSeveral laboratories have used cloned factor 8 DNA sequences as probes to characterized mutations that are responsible for hemophilia A in certain pedigrees. These mutations have been characterized by restriction analysis, oligonucleotide hybridization, cloning and sequencing of DNA from appropriate patientsIn about 500 patients with hemophilia A examined, the molecular defect has been recognized in 39. Both gross alterations (mainly deletions) and point mutations of the factor 8 gene have been found.A total of 19 different deletions have been observed. No two unrelated pedigrees share the same exact deletion.The size of the deleted DNA varies from 1.5 kb to more than 210 kb. All but one of these deletions are associated with severe hemophilia A. A deletion of 6 kb that contains exon 22 only is associated with moderate hemophilia. Some deletions are present in patients with inhibitors to factor 8. No correlation of the size or the position of the deletions can be found with the presence of inhibitors to factor 8.A total of 20 point mutations have been characterized. All are recognized by restriction analysis and involve Taq I sites. All are mutations of CpG dinucleotides and generate nonsense or missence codons. Unrelated pedigrees have the same single nucleotide change because of independent origin of the same mutation. In many instances de novo occurrence of a point mutation has been observed. CpG dinucleotides are hot spots for mutation to TG or CA presumably because of spontaneous deamination of methylcytosine. Some point mutations are present in patients with inhibitors but no correlation of the site of mutation and inhibitor formation has been found. The nonsense mutations are present in patients with severe hemophilia A. A missense mutation (Arg Gin) in exon 26 was found in a patient with mild hemophilia while another Arg Gin mutation in exon 24 has been observed in a patient with severe disease. The creation of a donor splice site in IVS 4 of factor 8 gene has been observed in a patient with mild hemophilia.Few DNA polymorphisms within the factor 8 gene and two other closely linked polymorphisms have been used for carrier detection and prenatal diagnosis of hemophilia A. These DNA markers are useful in more than 90% of families at risk for hemophilia A.The author thanks Drs. Gitschier, Din, Olek, Pirastou, Lawn for communication of their data prior to publication.The hemophilia project at Johns Hopkins was supported by an Institutional grant and NIH grant to S.S.A. and Haig H. Kazazian, Jr.
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Basharat, Zarrin, i Azra Yasmin. "Bioinformatic analysis of human Gαq Q209 missense mutations associated with uveal melanoma". W 2016 13th International Bhurban Conference on Applied Sciences and Technology (IBCAST). IEEE, 2016. http://dx.doi.org/10.1109/ibcast.2016.7429863.
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Nassiri, Isar, i Bahram Goliaei. "Computational analysis the influence of missense mutations upon protein structure and function". W the 1st ACM workshop. New York, New York, USA: ACM Press, 2009. http://dx.doi.org/10.1145/1531780.1531783.
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Cyganov, M. M., M. K. Ibragimova i A. A. Hozyainova. "PREDICTIVE AND PROGNOSTIC SIGNIFICANCE OF PALB2 GENE MUTATIONS IN BREAST TUMORS". W I International Congress “The Latest Achievements of Medicine, Healthcare, and Health-Saving Technologies”. Kemerovo State University, 2023. http://dx.doi.org/10.21603/-i-ic-146.
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It has been shown that the loss of PALB2 function, due to mutations or chromosomal
aberrations, may have an impact on the effectiveness of chemotherapy treatment and disease
prognosis in patients with various oncological diseases. Thus, the aim of this work was to
evaluate the predictive and prognostic potential of DNA copy number aberrations and PALB2
gene mutations in breast tumors.
Materials and methods. The study included 66 patients with breast cancer (BC). To
evaluate the presence of DNA copy number aberrations (CNA), microarray analysis was
used with the CytoScanTMHD Array high density microarrays. Gene mutations were
assessed by sequencing on the MiSeq™ Sequencing System using the Accel-Amplicon
BRCA1, BRCA2, and PALB2 Panel. Results. The presence of the PALB2 CNA gene is not
associated with the effectiveness of neoadjuvant chemotherapy (NAC), p=0.07. The
presence of a deletion is determined by 100% metastatic-free survival, versus 68% in the
group with normal copy number (log-rank test p=0.04). It has been established that
elimination of the frameshift deletion c.2552delA mutation during NAC leads to an
objective response to treatment. Identified missense mutations (c.2993G>A; c.2014G>C;
c.1010T>C) were observed in patients with tumor progression. But only c.1010T>C has
pathogenic significance. The presence of mutations in the PALB2 gene is not associated
with metastatic survival (log-rank test p=0.15). Conclusion. Currently, there is little data on
the impact of disorders in the PALB2 gene on the effectiveness of treatment and prognosis
of the disease, but the study of this gene has great potential for testing focused on diagnosis,
prevention, and a personalized approach to the treatment of cancer patients
Raporty organizacyjne na temat "Missense mutations"
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Weller, Joel I., Derek M. Bickhart, Micha Ron, Eyal Seroussi, George Liu i George R. Wiggans. Determination of actual polymorphisms responsible for economic trait variation in dairy cattle. United States Department of Agriculture, styczeń 2015. http://dx.doi.org/10.32747/2015.7600017.bard.
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The project’s general objectives were to determine specific polymorphisms at the DNA level responsible for observed quantitative trait loci (QTLs) and to estimate their effects, frequencies, and selection potential in the Holstein dairy cattle breed. The specific objectives were to (1) localize the causative polymorphisms to small chromosomal segments based on analysis of 52 U.S. Holstein bulls each with at least 100 sons with high-reliability genetic evaluations using the a posteriori granddaughter design; (2) sequence the complete genomes of at least 40 of those bulls to 20 coverage; (3) determine causative polymorphisms based on concordance between the bulls’ genotypes for specific polymorphisms and their status for a QTL; (4) validate putative quantitative trait variants by genotyping a sample of Israeli Holstein cows; and (5) perform gene expression analysis using statistical methodologies, including determination of signatures of selection, based on somatic cells of cows that are homozygous for contrasting quantitative trait variants; and (6) analyze genes with putative quantitative trait variants using data mining techniques. Current methods for genomic evaluation are based on population-wide linkage disequilibrium between markers and actual alleles that affect traits of interest. Those methods have approximately doubled the rate of genetic gain for most traits in the U.S. Holstein population. With determination of causative polymorphisms, increasing the accuracy of genomic evaluations should be possible by including those genotypes as fixed effects in the analysis models. Determination of causative polymorphisms should also yield useful information on gene function and genetic architecture of complex traits. Concordance between QTL genotype as determined by the a posteriori granddaughter design and marker genotype was determined for 30 trait-by-chromosomal segment effects that are segregating in the U.S. Holstein population; a probability of <10²⁰ was used to accept the null hypothesis that no segregating gene within the chromosomal segment was affecting the trait. Genotypes for 83 grandsires and 17,217 sons were determined by either complete sequence or imputation for 3,148,506 polymorphisms across the entire genome. Variant sites were identified from previous studies (such as the 1000 Bull Genomes Project) and from DNA sequencing of bulls unique to this project, which is one of the largest marker variant surveys conducted for the Holstein breed of cattle. Effects for stature on chromosome 11, daughter pregnancy rate on chromosome 18, and protein percentage on chromosome 20 met 3 criteria: (1) complete or nearly complete concordance, (2) nominal significance of the polymorphism effect after correction for all other polymorphisms, and (3) marker coefficient of determination >40% of total multiple-regression coefficient of determination for the 30 polymorphisms with highest concordance. The missense polymorphism Phe279Tyr in GHR at 31,909,478 base pairs on chromosome 20 was confirmed as the causative mutation for fat and protein concentration. For effect on fat percentage, 12 additional missensepolymorphisms on chromosome 14 were found that had nearly complete concordance with the suggested causative polymorphism (missense mutation Ala232Glu in DGAT1). The markers used in routine U.S. genomic evaluations were increased from 60,000 to 80,000 by adding markers for known QTLs and markers detected in BARD and other research projects. Objectives 1 and 2 were completely accomplished, and objective 3 was partially accomplished. Because no new clear-cut causative polymorphisms were discovered, objectives 4 through 6 were not completed.
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Weller, Joel I., Harris A. Lewin i Micha Ron. Determination of Allele Frequencies for Quantitative Trait Loci in Commercial Animal Populations. United States Department of Agriculture, luty 2005. http://dx.doi.org/10.32747/2005.7586473.bard.
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Individual loci affecting economic traits in dairy cattle (ETL) have been detected via linkage to genetic markers by application of the granddaughter design in the US population and the daughter design in the Israeli population. From these analyses it is not possible to determine allelic frequencies in the population at large, or whether the same alleles are segregating in different families. We proposed to answer this question by application of the "modified granddaughter design", in which granddaughters with a common maternal grandsire are both genotyped and analyzed for the economic traits. The objectives of the proposal were: 1) to fine map three segregating ETL previously detected by a daughter design analysis of the Israeli dairy cattle population; 2) to determine the effects of ETL alleles in different families relative to the population mean; 3) for each ETL, to determine the number of alleles and allele frequencies. The ETL on Bostaurusautosome (BT A) 6 chiefly affecting protein concentration was localized to a 4 cM chromosomal segment centered on the microsatellite BM143 by the daughter design. The modified granddaughter design was applied to a single family. The frequency of the allele increasing protein percent was estimated at 0.63+0.06. The hypothesis of equal allelic frequencies was rejected at p<0.05. Segregation of this ETL in the Israeli population was confirmed. The genes IBSP, SPP1, and LAP3 located adjacent to BM143 in the whole genome cattle- human comparative map were used as anchors for the human genome sequence and bovine BAC clones. Fifteen genes within 2 cM upstream of BM143 were located in the orthologous syntenic groups on HSA4q22 and HSA4p15. Only a single gene, SLIT2, was located within 2 cM downstream of BM143 in the orthologous HSA4p15 region. The order of these genes, as derived from physical mapping of BAC end sequences, was identical to the order within the orthologous syntenic groups on HSA4: FAM13A1, HERC3. CEB1, FLJ20637, PP2C-like, ABCG2, PKD2. SPP, MEP, IBSP, LAP3, EG1. KIAA1276, HCAPG, MLR1, BM143, and SLIT2. Four hundred and twenty AI bulls with genetic evaluations were genotyped for 12 SNPs identified in 10 of these genes, and for BM143. Seven SNPs displayed highly significant linkage disequilibrium effects on protein percentage (P<0.000l) with the greatest effect for SPP1. None of SNP genotypes for two sires heterozygous for the ETL, and six sires homozygous for the ETL completely corresponded to the causative mutation. The expression of SPP 1 and ABCG2 in the mammary gland corresponded to the lactation curve, as determined by microarray and QPCR assays, but not in the liver. Anti-sense SPP1 transgenic mice displayed abnormal mammary gland differentiation and milk secretion. Thus SPP 1 is a prime candidate gene for this ETL. We confirmed that DGAT1 is the ETL segregating on BTA 14 that chiefly effects fat concentration, and that the polymorphism is due to a missense mutation in an exon. Four hundred Israeli Holstein bulls were genotyped for this polymorphism, and the change in allelic frequency over the last 20 years was monitored.