MAT2A Mutations Predispose Individuals to Thoracic Aortic Aneurysms
MAT2A Mutations Predispose Individuals to Thoracic Aortic Aneurysms
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DOI：
10.1016/j.ajhg.2014.11.015
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发表时间：
2015-01-08
影响因子：
9.8
通讯作者：
Milewicz, Dianna M.
中科院分区：
文献类型：
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作者：
Guo, Dong-chuan;Gong, Limin;Milewicz, Dianna M.
高达20%的胸主动脉瘤或急性主动脉夹层但没有综合征特征的患者有胸主动脉疾病家族史。这种家族性疾病具有显著的遗传异质性。全基因组连锁分析和外显子组测序的远亲来自一个大的家庭，常染色体显性遗传的胸主动脉瘤的主动脉瓣相关的二叶主动脉瓣，用于识别其他基因易感个体这种情况。在MAT 2A中鉴定了一种罕见的变异体，c.1031A>C（p.Glu344Ala），其编码甲硫氨酸腺苷转移酶II α（MAT II α）。这种变异与家族中的疾病分离，并且桑格测序来自患有胸主动脉疾病的不相关家族的受影响先证者的DNA鉴定出另一种MAT 2A罕见变异，c.1067G>A（p.Arg356His）。这些变异使个体易患胸主动脉瘤和夹层的证据包括以下内容：人群中MAT 2A的罕见变异很少;从人类到斑马鱼，氨基酸Glu 344和Arg 356是保守的; MAT I α中这些氨基酸的取代见于高甲硫氨酸血症个体。结构分析表明，p.Glu344Ala和p.Arg356His破坏MAT II α酶的功能。通过吗啉寡聚体敲除斑马鱼的mat 2aa干扰心血管发育。共转染的野生型人MAT 2A mRNA以显著高于经编辑以表达Glu 344或Arg 356突变体的mRNA的水平挽救了斑马鱼心血管发育的缺陷，提供了p.Glu344Ala和p.Arg356His取代损害MAT II α功能的进一步证据。本文提供的数据支持以下结论：MAT 2A中的罕见遗传变异使个体易患胸主动脉疾病。
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.