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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 II alpha). 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 I alpha are found in individuals with hypermethioninemia. Structural analysis suggested that p.Glu344Ala and p.Arg356His disrupt MAT II alpha 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 II alpha function. The data presented here support the conclusion that rare genetic variants in MAT2A predispose individuals to thoracic aortic disease.
Keywords
METHIONINE ADENOSYLTRANSFERASE, VASCULAR SMOOTH-MUSCLE, S-ADENOSYLMETHIONINE, GENE-EXPRESSION, MARFAN-SYNDROME, DISSECTIONS, VALVE, VARIANTS, DEFICIENCY, SUBUNIT

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MLA
Guo, Dong-chuan et al. “MAT2A Mutations Predispose Individuals to Thoracic Aortic Aneurysms.” AMERICAN JOURNAL OF HUMAN GENETICS 96.1 (2015): 170–177. Print.
APA
Guo, D., Gong, L., Regalado, E. S., Santos-Cortez, R. L., Zhao, R., Cai, B., Veeraraghavan, S., et al. (2015). MAT2A Mutations predispose individuals to thoracic aortic aneurysms. AMERICAN JOURNAL OF HUMAN GENETICS, 96(1), 170–177.
Chicago author-date
Guo, Dong-chuan, Limin Gong, Ellen S Regalado, Regie L Santos-Cortez, Ren Zhao, Bo Cai, Sudha Veeraraghavan, et al. 2015. “MAT2A Mutations Predispose Individuals to Thoracic Aortic Aneurysms.” American Journal of Human Genetics 96 (1): 170–177.
Chicago author-date (all authors)
Guo, Dong-chuan, Limin Gong, Ellen S Regalado, Regie L Santos-Cortez, Ren Zhao, Bo Cai, Sudha Veeraraghavan, Siddharth K Prakash, Ralph J Johnson, Ann Muilenburg, Marcia Willing, Guillaume Jondeau, Catherine Boileau, Hariyadarshi Pannu, Rocio Moran, Julie De Backer, Michael J Bamshad, Jay Shendure, Deborah A Nickerson, Suzanne M Leal, CS Raman, Eric C Swindell, and Dianna M Milewicz. 2015. “MAT2A Mutations Predispose Individuals to Thoracic Aortic Aneurysms.” American Journal of Human Genetics 96 (1): 170–177.
Vancouver
1.
Guo D, Gong L, Regalado ES, Santos-Cortez RL, Zhao R, Cai B, et al. MAT2A Mutations predispose individuals to thoracic aortic aneurysms. AMERICAN JOURNAL OF HUMAN GENETICS. 2015;96(1):170–7.
IEEE
[1]
D. Guo et al., “MAT2A Mutations predispose individuals to thoracic aortic aneurysms,” AMERICAN JOURNAL OF HUMAN GENETICS, vol. 96, no. 1, pp. 170–177, 2015.
@article{5931183,
  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 II alpha). 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 I alpha are found in individuals with hypermethioninemia. Structural analysis suggested that p.Glu344Ala and p.Arg356His disrupt MAT II alpha 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 II alpha function. The data presented here support the conclusion that rare genetic variants in MAT2A predispose individuals to thoracic aortic disease.},
  author       = {Guo, Dong-chuan and Gong, Limin and Regalado, Ellen S and Santos-Cortez, Regie L and Zhao, Ren and Cai, Bo and Veeraraghavan, Sudha and Prakash, Siddharth K and Johnson, Ralph J and Muilenburg, Ann and Willing, Marcia and Jondeau, Guillaume and Boileau, Catherine and Pannu, Hariyadarshi and Moran, Rocio and De Backer, Julie and Bamshad, Michael J and Shendure, Jay and Nickerson, Deborah A and Leal, Suzanne M and Raman, CS and Swindell, Eric C and Milewicz, Dianna M},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  keywords     = {METHIONINE ADENOSYLTRANSFERASE,VASCULAR SMOOTH-MUSCLE,S-ADENOSYLMETHIONINE,GENE-EXPRESSION,MARFAN-SYNDROME,DISSECTIONS,VALVE,VARIANTS,DEFICIENCY,SUBUNIT},
  language     = {eng},
  number       = {1},
  pages        = {170--177},
  title        = {MAT2A Mutations predispose individuals to thoracic aortic aneurysms},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2014.11.015},
  volume       = {96},
  year         = {2015},
}

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