Mutations in DCHS1 cause mitral valve prolapse

被引：146

作者：

Durst, Ronen ^{[1
,2
,3
]}

Sauls, Kimberly ^{[4
]}

Peal, David S. ^{[5
]}

deVlaming, Annemarieke ^{[4
]}

Toomer, Katelynn ^{[4
]}

Leyne, Maire ^{[1
,2
]}

Salani, Monica ^{[1
,2
]}

Talkowski, Michael E. ^{[1
,2
,6
]}

Brand, Harrison ^{[1
,2
,6
]}

Perrocheau, Maelle ^{[7
]}

Simpson, Charles ^{[1
,2
]}

Jett, Christopher ^{[1
,2
]}

Stone, Matthew R. ^{[1
,2
]}

Charles, Florie ^{[1
,2
]}

Chiang, Colby ^{[1
,2
]}

Lynch, Stacey N. ^{[5
]}

Bouatia-Naji, Nabila ^{[7
,8
]}

Delling, Francesca N. ^{[9
]}

Freed, Lisa A. ^{[10
]}

Tribouilloy, Christophe ^{[11
,12
]}

Le Tourneau, Thierry ^{[13
,14
]}

LeMarec, Herve ^{[13
,14
]}

Fernandez-Friera, Leticia ^{[15
,16
]}

Solis, Jorge ^{[15
,16
]}

Trujillano, Daniel ^{[17
,18
,19
,20
]}

Ossowski, Stephan ^{[18
,21
]}

Estivill, Xavier ^{[17
,18
,19
,20
]}

Dina, Christian ^{[13
,14
,22
,23
,24
]}

Bruneval, Patrick ^{[25
]}

Chester, Adrian ^{[26
]}

Schott, Jean-Jacques ^{[13
,14
,22
,23
,24
]}

Irvine, Kenneth D. ^{[27
,28
]}

Mao, Yaopan ^{[27
,28
]}

Wessels, Andy ^{[4
]}

Motiwala, Tahirali ^{[4
]}

Puceat, Michel ^{[29
]}

Tsukasaki, Yoshikazu ^{[30
]}

Menick, Donald R. ^{[31
]}

Kasiganesan, Harinath ^{[31
]}

Nie, Xingju ^{[32
]}

Broome, Ann-Marie ^{[32
]}

Williams, Katherine ^{[4
]}

Johnson, Amanda ^{[4
]}

Markwald, Roger R. ^{[4
]}

Jeunemaitre, Xavier ^{[7
,8
,33
]}

Hagege, Albert ^{[7
,8
,34
]}

Levine, Robert A. ^{[8
,35
]}

Milan, David J. ^{[1
,2
,5
]}

Norris, Russell A. ^{[4
]}

Slaugenhaupt, Susan A. ^{[1
,2
]}

机构：

[1] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res,Res Inst, Boston, MA 02114 USA

[2] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02114 USA

[3] Hadassah Hebrew Univ, Med Ctr, Div Cardiol, Jerusalem, Israel

[4] Med Univ S Carolina, Childrens Res Inst, Cardiovasc Dev Biol Ctr, Dept Regenerat Med & Cell Biol,Dept Med, Charleston, SC 29425 USA

[5] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr,Cardiol Div, Boston, MA 02114 USA

[6] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA

[7] Paris Cardiovasc Res Ctr, INSERM, UMR 970, F-75015 Paris, France

[8] Univ Paris 05, Sorbonne Paris Cite, Fac Med, F-75006 Paris, France

[9] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med,Cardiovasc Div, Boston, MA 02215 USA

[10] Yale Univ, Sch Med, Heart & Vasc Ctr, Yale New Haven Hosp, New Haven, CT 06510 USA

[11] Univ Hosp Amiens, Dept Cardiol, F-80000 Amiens, France

[12] Jules Verne Univ Picardie, U 1088, INSERM, F-80000 Amiens, France

[13] INSERM, U1087, F-44007 Nantes, France

[14] Univ Hosp, Inst Thorax, F-44007 Nantes, France

[15] Ctr Nacl Invest Cardiovasc Carlos III CNIC, Madrid 28029, Spain

[16] Hosp Univ Monteprincipe, Madrid 28660, Spain

[17] Ctr Genom Regulat, Genet Causes Dis Grp, Barcelona 08003, Catalonia, Spain

[18] UPF, Barcelona 08002, Catalonia, Spain

[19] Hosp del Mar Med Res Inst IMIM, Barcelona 08003, Catalonia, Spain

[20] CIBER Epidemiol & Publ Hlth CIBERESP, Barcelona 08036, Catalonia, Spain

[21] CRG, Genom & Epigen Variat Dis Grp, Barcelona 08003, Catalonia, Spain

[22] CNRS, UMR 6291, F-44007 Nantes, France

[23] Univ Nantes, F-44322 Nantes, France

[24] CHU Nantes, Serv Cardiol, Inst Thorax, F-44093 Nantes, France

[25] Hop Europe Georges Pompidou, Serv Anat Pathol, F-75015 Paris, France

[26] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Heart Sci Ctr, London SW7 2AZ, England

[27] Rutgers State Univ, Waksman Inst, Howard Hughes Med Inst, Piscataway, NJ 08854 USA

[28] Rutgers State Univ, Dept Mol Biol & Biochem, Piscataway, NJ 08854 USA

[29] Aix Marseille Univ, Med Sch La Timone, Team Physiopathol Cardiac Dev, INSERM,UMR S910, F-13885 Marseille, France

[30] Univ Texas Hlth Ctr Tyler Northeast Tyler, Dept Cellular & Mol Biol, Tyler, TX 75708 USA

[31] Med Univ S Carolina, Div Cardiol, Dept Med, Gazes Cardiac Res Inst, Charleston, SC 29425 USA

[32] Med Univ S Carolina, Dept Radiol & Radiol Sci, Charleston, SC 29425 USA

[33] Hop Europeen Georges Pompidou, AP HP, AP HP, F-75015 Paris, France

[34] Hop Europeen Georges Pompidou, AP HP, Dept Cardiol, F-75015 Paris, France

[35] Harvard Univ, Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Div Cardiol, Boston, MA 02114 USA

来源：

NATURE | 2015年 / 525卷 / 7567期

基金：

美国国家卫生研究院; 美国国家科学基金会;

关键词：

ECHOCARDIOGRAPHIC EVIDENCE; FILAMIN-A; EXPRESSION; GENE; QUANTIFICATION; IDENTIFICATION; REGURGITATION; LOCUS; FAT;

D O I：

10.1038/nature14670

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals(1-3). It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery(4,5). 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.

引用

页码：109 / +

页数：18