Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals1,2,3. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery4,5. 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.
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This work was supported by the Fondation Leducq (Paris, France) Mitral Transatlantic Network of Excellence grant 07CVD04. MVP patient studies were supported by an Innovation in Clinical Research award of the Doris Duke Charitable Foundation, by an award of the Aetna Quality Care Research Fund, and by a gift from Rena M. Shulsky, New York, New York (S.A.S. and R.A.L.). Sequencing of the candidate region was performed at the Venter Institute through a grant from the National Heart Lung and Blood Institute Resequencing and Genotyping (RS&G) Service (S.A.S.). The work at MUSC was performed in a facility constructed with support from the National Institutes of Health, Grant Number C06 RR018823 from the Extramural Research Facilities Program of the National Center for Research Resources. Collection of the MVP France cohort was supported by the French Society of Cardiology. Other funding sources: National Heart Lung and Blood Institute: R01HL122906-01 (A.W.), R01-HL33756 (R.R.M.), COBRE 1P30 GM103342 (R.R.M., R.A.N., A.W.), 8P20 GM103444-07 (R.R.M. and R.A.N.), R01-HL109004 (D.J.M.), R01-HL127692 (D.J.M., S.A.S., R.A.N., R.A.L.); RO1-HL095696 (D.R.M.), VA Merit Review BX002327 (D.R.M.); National Institute of Mental Health R00-MH095867 (M.E.T.) The Hassenfeld Scholar Program (D.J.M.); The March of Dimes (M.E.T.); M.G.H. Scholars Program (S.A.S., M.E.T.); American Heart Association: 09GRNT2060075 (A.W.), 11SDG5270006 (R.A.N.), 2261354 (D.J.M.), 15GRNT25080052 (R.A.N.); National Science Foundation: EPS-0903795 (R.R.M.); NHLBI K24 HL67434, R01HL72265 and R01HL109506 and the Ellison Foundation, Boston, MA (R.A.L.), Howard Hughes Medical Institute (K.D.I.), and a gift from Michael Zak (D.J.M.). Thanks to T. Brown (MUSC) for his guidance on MRI studies, C. Hanscom (M.G.H.) for assistance with genomic libraries, and E. Lim (H.M.S.) for contributions in interpreting the exome mutation data. The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about.
Extended data figures
This video shows posterior leaflet prolapse and dilated left-heart chambers.
This video shows thickened, prolapsing leaflet in family 1 proband.
This video shows severe MR, increasing with prolapse throughout systole.
High-speed video of wild type (control injected) D. rerio heart at 72 hours post-fertilization (hpf).
At this stage the heart has looped and blood flow is unidirectional from the atrium (upper right) to the ventricle, and a constriction has formed at the junction between the atrium and ventricle. No regurgitation is evident.
Hearts of dchs1b morphants fail to loop properly and there is regurgitation of blood from the ventricle (lower right) into the atrium (upper left). Concomitant with this phenotype, there is reduced constriction of the AV canal.
This video shows normal mitral valve opening and closing.
This video shows anterior and posterior leaflet thickening and posterior leaflet prolapse. Prolapse is most easily observed at frames: 149, 188, and 300
This video comprises 2 clips, which show 3D reconstructions of Dchs1+/+ 9, and Dchs1+/- 9-month old posterior leaflet
Each of the clips shown were obtained from the micro-MRI slices.
Respective 3D reconstructions are shown sequentially during the movie. Green=Anterior Leaflet, Blue =Posterior Leaflet.
AMIRA 3D reconstruction of EPDC lineage trace in Dchs1+/+ and Dchs1+/- PO posterior mitral leaflets.
Respective 3D reconstructions are shown sequentially during the movie. Green=EPDC, Blue =non-EPDCs
About this article
Nature Communications (2016)