Identification of 2 Loci Associated with Development of Myxomatous Mitral Valve Disease in Cavalier King Charles Spaniels

Madsen, Majbritt Busk; Olsen, Lisbeth H.; Häggström, Jens; Höglund, Katja; Ljungvall, Ingrid; Falk, Torkel; Wess, Gerhard; Stephenson, Hannah; Dukes‐McEwan, J.; Chetboul, Valérie; Gouni, Vassiliki; Proschowsky, Helle Friis; Cirera, Susanna; Karlskov-Mortensen, Peter; Fredholm, Merete

doi:10.1093/jhered/esr041

Cited by 78 publications

(83 citation statements)

References 31 publications

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“…Myxomatous MV disease is most prevalent in small to medium-sized dog breeds. In King Charles cavalier spaniels, a GWAS identified loci associated with development of MVP in a 1.58 Mb region on CFA13 and a 1.68 Mb region on CFA14 40. More recently, a similar association study on whippet dogs identified new severity loci for MV degeneration on CFA15 and secondary loci of suggestive association on CFA2.…”

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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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: 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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“…173 Clues might also be gathered from correlative studies with heritable canine MVP, a cause of severe heart failure and mortality. 178,179 …”

Section: Mitral Valve Prolapsementioning

confidence: 99%

Mitral valve disease—morphology and mechanisms

Levine¹,

Hagège²,

Judge³

et al. 2015

Nat Rev Cardiol

309

254

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Mitral valve disease is a frequent cause of heart failure and death. Emerging evidence indicates that the mitral valve is not a passive structure, but—even in adult life—remains dynamic and accessible for treatment. This concept motivates efforts to reduce the clinical progression of mitral valve disease through early detection and modification of underlying mechanisms. Discoveries of genetic mutations causing mitral valve elongation and prolapse have revealed that growth factor signalling and cell migration pathways are regulated by structural molecules in ways that can be modified to limit progression from developmental defects to valve degeneration with clinical complications. Mitral valve enlargement can determine left ventricular outflow tract obstruction in hypertrophic cardiomyopathy, and might be stimulated by potentially modifiable biological valvular–ventricular interactions. Mitral valve plasticity also allows adaptive growth in response to ventricular remodelling. However, adverse cellular and mechanobiological processes create relative leaflet deficiency in the ischaemic setting, leading to mitral regurgitation with increased heart failure and mortality. Our approach, which bridges clinicians and basic scientists, enables the correlation of observed disease with cellular and molecular mechanisms, leading to the discovery of new opportunities for improving the natural history of mitral valve disease.

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“…A similar disease has a very high prevalence in Cavalier King Charles spaniels and GWAS conducted with 100 cases and 100 controls have recently identified two novel candidate regions. Studies are currently underway to identify the causative gene and mutation within the regions (Madsen et al, 2011).…”

Section: Myxomatous Mitral Valve Diseasementioning

confidence: 99%

LUPA: A European initiative taking advantage of the canine genome architecture for unravelling complex disorders in both human and dogs

Lequarré

Andersson

André

et al. 2011

The Veterinary Journal

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a b s t r a c tThe domestic dog offers a unique opportunity to explore the genetic basis of disease, morphology and behaviour. Humans share many diseases with our canine companions, making dogs an ideal model organism for comparative disease genetics. Using newly developed resources, genome-wide association studies in dog breeds are proving to be exceptionally powerful. Towards this aim, veterinarians and geneticists from 12 European countries are collaborating to collect and analyse the DNA from large cohorts of dogs suffering from a range of carefully defined diseases of relevance to human health. This project, named LUPA, has already delivered considerable results. The consortium has collaborated to develop a new high density single nucleotide polymorphism (SNP) array. Mutations for four monogenic diseases have been identified and the information has been utilised to find mutations in human patients. Several complex diseases have been mapped and fine mapping is underway. These findings should ultimately lead to a better understanding of the molecular mechanisms underlying complex diseases in both humans and their best friend.

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Identification of 2 Loci Associated with Development of Myxomatous Mitral Valve Disease in Cavalier King Charles Spaniels

Cited by 78 publications

References 31 publications

Genetics of syndromic and non-syndromic mitral valve prolapse

Genetics of syndromic and non-syndromic mitral valve prolapse

Mitral valve disease—morphology and mechanisms

LUPA: A European initiative taking advantage of the canine genome architecture for unravelling complex disorders in both human and dogs

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