Durst Ronen, Sauls Kimberly, Peal David S, deVlaming Annemarieke, Toomer Katelynn, Leyne Maire, Salani Monica, Talkowski Michael E, Brand Harrison, Perrocheau Maëlle, Simpson Charles, Jett Christopher, Stone Matthew R, Charles Florie, Chiang Colby, Lynch Stacey N, Bouatia-Naji Nabila, Delling Francesca N, Freed Lisa A, Tribouilloy Christophe, Le Tourneau Thierry, LeMarec Hervé, Fernandez-Friera Leticia, Solis Jorge, Trujillano Daniel, Ossowski Stephan, Estivill Xavier, Dina Christian, Bruneval Patrick, Chester Adrian, Schott Jean-Jacques, Irvine Kenneth D, Mao Yaopan, Wessels Andy, Motiwala Tahirali, Puceat Michel, Tsukasaki Yoshikazu, Menick Donald R, Kasiganesan Harinath, Nie Xingju, Broome Ann-Marie, Williams Katherine, Johnson Amanda, Markwald Roger R, Jeunemaitre Xavier, Hagege Albert, Levine Robert A, Milan David J, Norris Russell A, Slaugenhaupt Susan A
Center for Human Genetic Research, Massachusetts General Hospital Research Institute and Department of Neurology, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114 USA.
Cardiology Division, Hadassah Hebrew University Medical Center, POB 12000 Jerusalem, Israel.
Nature. 2015 Sep 3;525(7567):109-13. doi: 10.1038/nature14670. Epub 2015 Aug 10.
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 aetiology 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 homologue dachsous1b resulted in a cardiac atrioventricular canal defect that could be rescued by wild-type human DCHS1, but not by DCHS1 messenger RNA 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 aetiological 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.
二尖瓣脱垂（MVP）是一种常见的心脏瓣膜疾病，每40人中就有近1人受其影响。它可表现为二尖瓣反流，是二尖瓣手术的主要指征。尽管有明确的遗传因素，但导致非综合征性MVP的遗传病因仍不清楚。一个多代同堂的大家庭中有4名受非综合征性MVP影响的个体，对其11号染色体上的连锁区间进行了捕获测序。我们报告了DCHS1基因中的一个错义突变，该基因是果蝇细胞极性基因dachsous（ds）的人类同源基因，在这个家族中与MVP共分离。对斑马鱼同源基因dachsous1b进行吗啉代敲低，导致心脏房室管缺陷，野生型人类DCHS1可挽救该缺陷，但携带家族性突变的DCHS1信使核糖核酸则不能。进一步的遗传学研究又发现了另外两个家族，其中第二个有害的DCHS1突变与MVP共分离。正如在斑马鱼、培养细胞中，尤其是在先证者二尖瓣修复手术中获得的二尖瓣间质细胞（MVIC）中所证明的那样，这两个DCHS1突变都会降低蛋白质稳定性。Dchs1(+/-)小鼠出现增厚的二尖瓣脱垂，这可追溯到瓣膜形态发生过程中的发育错误。MVP患者MVIC以及Dchs1(+/-)小鼠MVIC中DCHS1的缺乏，导致迁移和细胞模式改变，支持这些过程是该疾病的病因基础。了解DCHS1在二尖瓣发育和MVP发病机制中的作用，可能为这种非常常见的疾病带来治疗方面的见解。
