Genetic association analyses highlight biological pathways underlying mitral valve prolapse

Dina, Christian; Bouatia-Naji, Nabila; Tucker, Nathan R.; Delling, Francesca N.; Toomer, Katelynn; Durst, Ronen; Perrocheau, Maëlle; Fernández‐Friera, Leticia; Solı́s, Jorge; Tourneau, Thierry Le; Chen, Ming-Huei; Probst, Vincent; Bossé, Yohan; Pîbarot, Philippe; Zélénika, Diana; Lathrop, Mark; Herçberg, Serge; Roussel, Ronan; Benjamin, Emelia J.; Bonnet, Fabrice; Lo, Su Hao; Dolmatova, Elena; Simonet, Floriane; Lecointe, Simon; Kyndt, Florence; Redon, Richard; Marec, Hervé Le; Froguel, Philippe; Ellinor, Patrick T.; Vasan, Ramachandran S.; Bruneval, Patrick; Markwald, Roger R.; Norris, Russell A.; Milan, David J.; Slaugenhaupt, Susan A.; Levine, Robert A.; Schott, Jean‐Jacques; Hagège, Albert; Jeunemaı̂tre, Xavier

doi:10.1038/ng.3383

Cited by 119 publications

(133 citation statements)

References 38 publications

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“…In 2015, Dina et al conducted a GWAS including 1412 isolated MVP cases and 2439 controls 39. Three loci showed genome-wide significant associations with MVP, respectively, at 2q35, 17p13 and 22q12.…”

Section: Genetics Of Isolated Mvp: Common Risk Alleles For Mvpmentioning

confidence: 99%

“…Genetically engineered mice mimicking syndromic forms of MVP have been reported for FBN1 ,42 PTPN11 , ADAMTS12 , TGβR1 , TGβR2 and SMAD-4 , and also for non-syndromic MVP such as FLNA ,43 44 DCHS1 and TNS1 39. Furthermore, structural or functional abnormalities of the MV have been described in a series of genetically engineered mice models (http://www.mousemine.org/mousemine/begin.do) (table 2).…”

Section: Animal Models and Mvpmentioning

confidence: 99%

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Genetics of syndromic and non-syndromic mitral valve prolapse

Tourneau¹,

Mérot

Rimbert

et al. 2018

Heart

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Mitral valve prolapse (MVP) is a common condition that affects 2%–3% of the general population. MVP is thought to include syndromic forms such as Marfan syndrome and non-syndromic MVP, which is the most frequent form. Myxomatous degeneration and fibroelastic deficiency (FED) are regarded as two different forms of non-syndromic MVP. While FED is still considered a degenerative disease associated with ageing, frequent familial clustering has been demonstrated for myxomatous MVP. Familial and genetic studies led to the recognition of reduced penetrance and large phenotypic variability, and to the identification of prodromal or atypical forms as a part of the complex spectrum of the disease. Whereas autosomal dominant mode is the common inheritance pattern, an X linked form of non-syndromic MVP was recognised initially, related to Filamin-A gene, encoding for a cytoskeleton protein involved in mechanotransduction. This identification allowed a comprehensive description of a new subtype of MVP with a unique association of leaflet prolapse and paradoxical restricted motion in diastole. In autosomal dominant forms, three loci have been mapped to chromosomes 16p11-p12, 11p15.4 and 13q31–32. Although deciphering the underlying genetic defects is still a work in progress, DCHS1 mutations have been identified (11p15.4) in typical myxomatous disease, highlighting new molecular pathways and pathophysiological mechanisms leading to the development of MVP. Finally, a large international genome-wide association study demonstrated the implication of frequent variants in MVP development and opened new directions for future research. Hence, this review focuses on phenotypic, genetic and pathophysiological aspects of MVP.

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Section: Genetics Of Isolated Mvp: Common Risk Alleles For Mvpmentioning

confidence: 99%

Section: Animal Models and Mvpmentioning

confidence: 99%

Genetics of syndromic and non-syndromic mitral valve prolapse

Tourneau¹,

Mérot

Rimbert

et al. 2018

Heart

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“…Although some valvular heart defects have been linked to specific genetic mutations (e.g. in NOTCH1, TBX5, GATA4, TBX20, LMCD1, TNS1 and DCHS1 (Dina et al, 2015; Durst et al, 2015; Garg et al, 2005; Richards and Garg, 2010; Theodoris et al, 2015), the majority have no clearly definable genetic or environmental cause (Levine et al, 2015). Thus, it is thought that epigenetic factors play an important role in the pathogenesis of congenital valve defects.…”

Section: Introductionmentioning

confidence: 99%

Hemodynamic Forces Sculpt Developing Heart Valves through a KLF2-WNT9B Paracrine Signaling Axis

et al. 2017

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Summary Hemodynamic forces play an essential epigenetic role in heart valve development, but how they do so is not known. Here we show that the shear-responsive transcription factor KLF2 is required in endocardial cells to regulate the mesenchymal cell responses that remodel cardiac cushions to mature valves. Endocardial Klf2 deficiency results in defective valve formation associated with loss of Wnt9b expression and reduced canonical WNT signaling in neighboring mesenchymal cells, a phenotype reproduced by endocardial-specific loss of Wnt9b. Studies in zebrafish embryos reveal that wnt9b expression is similarly restricted to the endocardial cells overlying the developing heart valves and dependent upon both hemodynamic shear forces and klf2a expression. These studies identify KLF2-WNT9B signaling as a conserved molecular mechanism by which fluid forces sensed by endothelial cells direct the complex cellular process of heart valve development, and suggest that congenital valve defects may arise due to subtle defects in this mechanotransduction pathway.

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“…Recent work from the Leducq MITRAL Network analyzing 1,412 mitral prolapse cases compared with 2,439 controls revealed a LMCD1 (LM and cysteine-rich domains 1), which encodes a transcription factor associated with atrioventricular valve regurgitation (7). Familial analysis has also implicated DCHS1 and beta-adrenergic receptor polymorphisms as playing a role in mitral prolapse (8,9).…”

mentioning

confidence: 99%

The evolution of mitral valve prolapse: insights from the Framingham Heart Study

et al. 2016

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The Framingham Heart Study group has described the non-diagnostic variants may evolve into mitral valve prolapse over time. These non-diagnostic variants include minimal systolic displacement, and abnormal anterior coaptation which is measured on surface echocardiography. Computed tomography and cardiac magnetic resonance imaging are evolving and can assess the degree of mitral regurgitation (MR); imaging techniques aside, genetic and proteomic detection of mitral prolapse is also evolving. However, the genetic basis for mitral prolapse is complex and likely involves multiple genetic loci. The same is also true for work determining possible biomarkers associated with mitral prolapse. The present study may be useful in counseling patients with a family history of mitral prolapse. Registry data is therefore of paramount importance in providing unbiased insight into this common disease.

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Genetic association analyses highlight biological pathways underlying mitral valve prolapse

Cited by 119 publications

References 38 publications

Genetics of syndromic and non-syndromic mitral valve prolapse

Genetics of syndromic and non-syndromic mitral valve prolapse

Hemodynamic Forces Sculpt Developing Heart Valves through a KLF2-WNT9B Paracrine Signaling Axis

The evolution of mitral valve prolapse: insights from the Framingham Heart Study

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