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Am J Hum Genet. 2015 Jan 8;96(1):170-7. doi: 10.1016/j.ajhg.2014.11.015. Epub 2014 Dec 31.

MAT2A mutations predispose individuals to thoracic aortic aneurysms.

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Department of Internal Medicine, University of Texas Health Science Center, Houston, TX 77030, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA.
University of Iowa, Iowa City, IA 52242, USA.
School of Medicine, Washington University, St. Louis, MO 63110, USA.
Centre National de Référence pour le Syndrome de Marfan et Apparentés, Hôpital Bichat, 75018 Paris, France.
INSERM U383, Hôpital Necker-Enfants Malades, Université Paris, 75018 Paris, France.
Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Department of Pediatrics, University of Texas Health Science Center, Houston, TX 77030, USA.
Department of Internal Medicine, University of Texas Health Science Center, Houston, TX 77030, USA. Electronic address:


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.

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