دورية أكاديمية
أعرض في EDS

MAT2A mutations predispose individuals to thoracic aortic aneurysms.

التفاصيل البيبلوغرافية
العنوان: MAT2A mutations predispose individuals to thoracic aortic aneurysms.
المؤلفون: Guo DC; Department of Internal Medicine, University of Texas Health Science Center, Houston, TX 77030, USA., Gong L; Department of Internal Medicine, University of Texas Health Science Center, Houston, TX 77030, USA., Regalado ES; Department of Internal Medicine, University of Texas Health Science Center, Houston, TX 77030, USA., Santos-Cortez RL; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Zhao R; Department of Internal Medicine, University of Texas Health Science Center, Houston, TX 77030, USA., Cai B; Department of Internal Medicine, University of Texas Health Science Center, Houston, TX 77030, USA., Veeraraghavan S; School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA., Prakash SK; Department of Internal Medicine, University of Texas Health Science Center, Houston, TX 77030, USA., Johnson RJ; Department of Internal Medicine, University of Texas Health Science Center, Houston, TX 77030, USA., Muilenburg A; University of Iowa, Iowa City, IA 52242, USA., Willing M; School of Medicine, Washington University, St. Louis, MO 63110, USA., Jondeau G; Centre National de Référence pour le Syndrome de Marfan et Apparentés, Hôpital Bichat, 75018 Paris, France., Boileau C; INSERM U383, Hôpital Necker-Enfants Malades, Université Paris, 75018 Paris, France., Pannu H; Department of Internal Medicine, University of Texas Health Science Center, Houston, TX 77030, USA., Moran R; Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA., Debacker J; Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium., Bamshad MJ; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA., Shendure J; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA., Nickerson DA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA., Leal SM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Raman CS; School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA., Swindell EC; Department of Pediatrics, University of Texas Health Science Center, Houston, TX 77030, USA., Milewicz DM; Department of Internal Medicine, University of Texas Health Science Center, Houston, TX 77030, USA. Electronic address: dianna.m.milewicz@uth.tmc.edu.
مؤلفون مشاركون: GenTAC Investigators, National Heart, Lung, and Blood Institute Go Exome Sequencing Project, Montalcino Aortic Consortium
المصدر: American journal of human genetics [Am J Hum Genet] 2015 Jan 08; Vol. 96 (1), pp. 170-7. Date of Electronic Publication: 2014 Dec 31.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Cell Press Country of Publication: United States NLM ID: 0370475 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1537-6605 (Electronic) Linking ISSN: 00029297 NLM ISO Abbreviation: Am J Hum Genet Subsets: MEDLINE
أسماء مطبوعة: Publication: 2008- : [Cambridge, MA] : Cell Press
Original Publication: Baltimore, American Society of Human Genetics.
مواضيع طبية MeSH: Aortic Aneurysm, Thoracic/*genetics , Methionine Adenosyltransferase/*genetics, Adolescent ; Adult ; Amino Acid Sequence ; Aortic Dissection/genetics ; Animals ; Aortic Valve/abnormalities ; Bicuspid Aortic Valve Disease ; Exome ; Female ; Genetic Linkage ; Genetic Predisposition to Disease ; Genetic Variation ; Genotype ; Heart Valve Diseases/genetics ; Humans ; Male ; Methionine Adenosyltransferase/metabolism ; Middle Aged ; Mutation ; Pedigree ; Protein Conformation ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Young Adult ; Zebrafish/genetics
مستخلص: Up to 20% of individuals who have thoracic aortic aneurysms or acute aortic dissections but who do not have syndromic features have a family history of thoracic aortic disease. Significant genetic heterogeneity is established for this familial condition. Whole-genome linkage analysis and exome sequencing of distant relatives from a large family with autosomal-dominant inheritance of thoracic aortic aneurysms variably associated with the bicuspid aortic valve was used for identification of additional genes predisposing individuals to this condition. A rare variant, c.1031A>C (p.Glu344Ala), was identified in MAT2A, which encodes methionine adenosyltransferase II alpha (MAT IIα). This variant segregated with disease in the family, and Sanger sequencing of DNA from affected probands from unrelated families with thoracic aortic disease identified another MAT2A rare variant, c.1067G>A (p.Arg356His). Evidence that these variants predispose individuals to thoracic aortic aneurysms and dissections includes the following: there is a paucity of rare variants in MAT2A in the population; amino acids Glu344 and Arg356 are conserved from humans to zebrafish; and substitutions of these amino acids in MAT Iα are found in individuals with hypermethioninemia. Structural analysis suggested that p.Glu344Ala and p.Arg356His disrupt MAT IIα enzyme function. Knockdown of mat2aa in zebrafish via morpholino oligomers disrupted cardiovascular development. Co-transfected wild-type human MAT2A mRNA rescued defects of zebrafish cardiovascular development at significantly higher levels than mRNA edited to express either the Glu344 or Arg356 mutants, providing further evidence that the p.Glu344Ala and p.Arg356His substitutions impair MAT IIα function. The data presented here support the conclusion that rare genetic variants in MAT2A predispose individuals to thoracic aortic disease.
(Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
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معلومات مُعتمدة: RC2 HL102923 United States HL NHLBI NIH HHS; UC2 HL102926 United States HL NHLBI NIH HHS; UC2 HL103010 United States HL NHLBI NIH HHS; HL-103010 United States HL NHLBI NIH HHS; RC2 HL102926 United States HL NHLBI NIH HHS; R01 HL062594 United States HL NHLBI NIH HHS; HL-102924 United States HL NHLBI NIH HHS; RC2 HL102924 United States HL NHLBI NIH HHS; HL-102926 United States HL NHLBI NIH HHS; UL1 RR024148 United States RR NCRR NIH HHS; UC2 HL102923 United States HL NHLBI NIH HHS; UC2 HL102924 United States HL NHLBI NIH HHS; HL-102925 United States HL NHLBI NIH HHS; KL2 TR000370 United States TR NCATS NIH HHS; RC2 HL103010 United States HL NHLBI NIH HHS; R01 HL62594 United States HL NHLBI NIH HHS; HL-102923 United States HL NHLBI NIH HHS; P01HL110869-01 United States HL NHLBI NIH HHS; P01 HL110869 United States HL NHLBI NIH HHS; RC2 HL102925 United States HL NHLBI NIH HHS; UC2 HL102925 United States HL NHLBI NIH HHS; UL1 TR000371 United States TR NCATS NIH HHS; R01 HL109942 United States HL NHLBI NIH HHS
المشرفين على المادة: 0 (RNA, Messenger)
EC 2.5.1.6 (MAT2A protein, human)
EC 2.5.1.6 (Methionine Adenosyltransferase)
تواريخ الأحداث: Date Created: 20150106 Date Completed: 20150314 Latest Revision: 20221207
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC4289682
DOI: 10.1016/j.ajhg.2014.11.015
PMID: 25557781
قاعدة البيانات: MEDLINE
الوصف
تدمد:1537-6605
DOI:10.1016/j.ajhg.2014.11.015