MAT2A Mutations Predispose Individuals to Thoracic Aortic Aneurysms
| Autor: | Ralph J. Johnson, Guillaume Jondeau, Dongchuan Guo, Ren Zhao, Marcia C. Willing, Limin Gong, Bo Cai, Michael J. Bamshad, C. S. Raman, Rocio Moran, Catherine Boileau, Dianna M. Milewicz, Siddharth K. Prakash, Sudha Veeraraghavan, Ellen S. Regalado, Ann Muilenburg, Eric C. Swindell, Suzanne M. Leal, Deborah A. Nickerson, Julie Debacker, Jay Shendure, Hariyadarshi Pannu, Regie Lyn P. Santos-Cortez |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Marfan syndrome Aortic valve Genetic Linkage Protein Conformation Heart Valve Diseases 030204 cardiovascular system & hematology Aortic aneurysm 0302 clinical medicine Bicuspid aortic valve Bicuspid Aortic Valve Disease Exome Genetics(clinical) Zebrafish Genetics (clinical) Exome sequencing Genetics 0303 health sciences education.field_of_study Middle Aged Pedigree medicine.anatomical_structure Aortic Valve cardiovascular system Female Adult Adolescent Genotype Population Biology Young Adult 03 medical and health sciences Aneurysm Report medicine Animals Humans Genetic Predisposition to Disease Amino Acid Sequence RNA Messenger education 030304 developmental biology Aortic Aneurysm Thoracic Genetic Variation Methionine Adenosyltransferase medicine.disease Aortic Dissection Mutation |
| Zdroj: | The American Journal of Human Genetics. 96(1):170-177 |
| ISSN: | 0002-9297 |
| DOI: | 10.1016/j.ajhg.2014.11.015 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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