Mutations in DCHS1 cause mitral valve prolapse.
Mutations in DCHS1 cause mitral valve prolapse.
复制标题
DOI：
10.1038/nature14670
复制
发表时间：
2015-09-03
期刊：
影响因子：
64.8
通讯作者：
Slaugenhaupt SA
中科院分区：
文献类型：
--
作者：
Durst R;Sauls K;Peal DS;deVlaming A;Toomer K;Leyne M;Salani M;Talkowski ME;Brand H;Perrocheau M;Simpson C;Jett C;Stone MR;Charles F;Chiang C;Lynch SN;Bouatia-Naji N;Delling FN;Freed LA;Tribouilloy C;Le Tourneau T;LeMarec H;Fernandez-Friera L;Solis J;Trujillano D;Ossowski S;Estivill X;Dina C;Bruneval P;Chester A;Schott JJ;Irvine KD;Mao Y;Wessels A;Motiwala T;Puceat M;Tsukasaki Y;Menick DR;Kasiganesan H;Nie X;Broome AM;Williams K;Johnson A;Markwald RR;Jeunemaitre X;Hagege A;Levine RA;Milan DJ;Norris RA;Slaugenhaupt SA
二尖瓣脱垂（MVP）是一种常见的心脏瓣膜疾病，影响近1/40的个体。它可以表现为二尖瓣返流，是二尖瓣手术的主要适应症。尽管有明确的遗传因素，但导致非综合征型MVP的遗传病因仍然难以捉摸。四个受影响的个人从一个大的多代家庭分离非综合征MVP进行捕获测序的连锁区间11号染色体。我们报告了一个错义突变DCHS 1基因，人类同源的果蝇细胞极性基因dachsous（ds），分离与MVP的家庭。Morpholino敲除斑马鱼同源物dachsous 1b导致心脏房室管缺陷，可以通过野生型人DCHS 1挽救，但不能通过家族性突变的DCHS 1 mRNA。进一步的遗传学研究确定了另外两个家族，其中第二个有害的DCHS 1突变与MVP分离。两种DCHS 1突变都降低了蛋白质的稳定性，如在斑马鱼、培养细胞中所证明的，特别是在先证者的二尖瓣修复手术期间获得的二尖瓣间质细胞（MVIC）中所证明的。Dchs 1 +/−小鼠有增厚的二尖瓣小叶脱垂，这可以追溯到瓣膜形态发生的发育错误。MVP患者MVIC以及Dchs 1 +/−小鼠MVIC中的DCHS 1缺陷导致迁移和细胞模式改变，支持这些过程作为疾病的病因学基础。了解DCHS 1在二尖瓣发育和MVP发病机制中的作用，为这种非常常见的疾病的治疗提供了可能。
Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery. Despite a clear heritable component, the genetic etiology leading to non-syndromic MVP has remained elusive. Four affected individuals from a large multigenerational family segregating non-syndromic MVP underwent capture sequencing of the linked interval on chromosome 11. We report a missense mutation in the DCHS1 gene, the human homologue of the Drosophila cell polarity gene dachsous (ds) that segregates with MVP in the family. Morpholino knockdown of the zebrafish homolog dachsous1b resulted in a cardiac atrioventricular canal defect that could be rescued by wild-type human DCHS1, but not by DCHS1 mRNA with the familial mutation. Further genetic studies identified two additional families in which a second deleterious DCHS1 mutation segregates with MVP. Both DCHS1 mutations reduce protein stability as demonstrated in zebrafish, cultured cells, and, notably, in mitral valve interstitial cells (MVICs) obtained during mitral valve repair surgery of a proband. Dchs1+/− mice had prolapse of thickened mitral leaflets, which could be traced back to developmental errors in valve morphogenesis. DCHS1 deficiency in MVP patient MVICs as well as in Dchs1+/− mouse MVICs result in altered migration and cellular patterning, supporting these processes as etiological underpinnings for the disease. Understanding the role of DCHS1 in mitral valve development and MVP pathogenesis holds potential for therapeutic insights for this very common disease.
影响因子：
1.8
作者：
Li K;Stockwell TB
通讯作者：
Stockwell TB