Mutations in DCHS1 cause mitral valve prolapse

Ronen Durst, Kimberly Sauls, David S. Peal, Annemarieke DeVlaming, Katelynn Toomer, Maire Leyne, Monica Salani, Michael E. Talkowski, Harrison Brand, Maëlle Perrocheau, Charles Simpson, Christopher Jett, Matthew R. Stone, Florie Charles, Colby Chiang, Stacey N. Lynch, Nabila Bouatia-Naji, Francesca N. Delling, Lisa A. Freed, Christophe TribouilloyThierry Le Tourneau, Hervé LeMarec, Leticia Fernandez-Friera, Jorge Solis, Daniel Trujillano, Stephan Ossowski, Xavier P. Estivill, Christian Dina, Patrick Bruneval, Adrian Chester, Jean Jacques Schott, Kenneth D. Irvine, Yaopan Mao, Andy Wessels, Tahirali Motiwala, Michel Puceat, Yoshikazu Tsukasaki, Donald R. Menick, Harinath Kasiganesan, Xingju Nie, Ann Marie Broome, Katherine Williams, Amanda Johnson, Roger R. Markwald, Xavier Jeunemaitre, Albert Hagege, Robert A. Levine, David J. Milan, Russell A. Norris, Susan A. Slaugenhaupt

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Abstract

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.

Original languageEnglish
Pages (from-to)109-113
Number of pages5
JournalNature
Volume525
Issue number7567
DOIs
Publication statusPublished - 3 Sep 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Durst, R., Sauls, K., Peal, D. S., DeVlaming, A., Toomer, K., Leyne, M., Salani, M., Talkowski, M. E., Brand, H., Perrocheau, M., Simpson, C., Jett, C., Stone, M. R., Charles, F., Chiang, C., Lynch, S. N., Bouatia-Naji, N., Delling, F. N., Freed, L. A., ... Slaugenhaupt, S. A. (2015). Mutations in DCHS1 cause mitral valve prolapse. Nature, 525(7567), 109-113. https://doi.org/10.1038/nature14670