PUBLICATION

MAT2A Mutations Predispose Individuals to Thoracic Aortic Aneurysms

Authors
Guo, D., Gong, L., Regalado, E.S., Santos-Cortez, R.L., Zhao, R., Cai, B., Veeraraghavan, S., Prakash, S.K., Johnson, R.J., Muilenburg, A., Willing, M., Jondeau, G., Boileau, C., Pannu, H., Moran, R., Debacker, J., Bamshad, M.J., Shendure, J., Nickerson, D.A., Leal, S.M., Raman, C.S., Swindell, E.C., Milewicz, D.M.
ID
ZDB-PUB-150106-4
Date
2015
Source
American journal of human genetics   96(1): 170-7 (Journal)
Registered Authors
Swindell, Eric C.
Keywords
none
MeSH Terms
  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Animals
  • Aortic Aneurysm, Thoracic/genetics*
  • Aortic Dissection/genetics
  • Aortic Valve/abnormalities
  • Exome
  • Female
  • Genetic Linkage
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Genotype
  • Heart Valve Diseases/genetics
  • Humans
  • Male
  • Methionine Adenosyltransferase/genetics*
  • Methionine Adenosyltransferase/metabolism
  • Middle Aged
  • Mutation
  • Pedigree
  • Protein Conformation
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Young Adult
  • Zebrafish/genetics
PubMed
25557781 Full text @ Am. J. Hum. Genet.
Abstract
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping