The R820W mutation in the MYBPC3 gene, associated with hypertrophic cardiomyopathy in cats, causes hypertrophic cardiomyopathy and left ventricular non-compaction in humans

Ripoll‐Vera, Tomás; Monserrat, Lorenzo; Prieto, Manuel Hermida; Ortiz, Martín; García, Isabel Rodríguez; Callizo, Nancy Govea; Navarro, Carlos Gómez; Andreo, Jordi Rosell; Martínez, José María Gámez; Lladó, Guillermo Pons; Luengos, D Cremer; Marqués, Joan Torres

doi:10.1016/j.ijcard.2010.04.032

Cited by 38 publications

(19 citation statements)

References 8 publications

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“…3 Interestingly, the R820W mutation along with an R820Q variant have also been identified in human patients with HCM. 99,100 Once again the nucleotide sequence in this region of the MYBPC3 gene was highly conserved across mammalian species (human, mouse, rat, dog, cow). Of the 20 cats studied, 9 were homozygous for this mutation.…”

Section: Feline Hcmmentioning

confidence: 96%

The genetic basis of hypertrophic cardiomyopathy in cats and humans

Kittleson

Meurs

Harris

2015

Journal of Veterinary Cardiology

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Section: Feline Hcmmentioning

confidence: 96%

The genetic basis of hypertrophic cardiomyopathy in cats and humans

Kittleson

Meurs

Harris

2015

Journal of Veterinary Cardiology

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“…In both breeds, a homozygous mutation in MYBPC3 was identified resulting in amino acid substitution—A31P and R820W in Maine Coons and Ragdolls, respectively (Meurs et al, 2005, 2007). The same R820W mutation has been identified in a human family which exhibits an almost identical phenotype to Ragdoll cats with severe left ventricular wall hypertrophy, arrhythmia, congestive heart failure and sudden cardiac death in homozygotes and only mild and very late expression in heterozygous carriers (Ripoll Vera et al, 2010; Borgeat et al, 2014). Despite analysis of candidate genes in a number of other pedigree breeds no other mutations have been identified to date (Meurs et al, 2009).…”

Section: Introductionmentioning

confidence: 86%

Investigations into the Sarcomeric Protein and Ca2+-Regulation Abnormalities Underlying Hypertrophic Cardiomyopathy in Cats (Felix catus)

et al. 2017

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Hypertrophic cardiomyopathy (HCM) is the most common single gene inherited cardiomyopathy. In cats (Felix catus) HCM is even more prevalent and affects 16% of the outbred population and up to 26% in pedigree breeds such as Maine Coon and Ragdoll. Homozygous MYBPC3 mutations have been identified in these breeds but the mutations in other cats are unknown. At the clinical and physiological level feline HCM is closely analogous to human HCM but little is known about the primary causative mechanism. Most identified HCM causing mutations are in the genes coding for proteins of the sarcomere. We therefore investigated contractile and regulatory proteins in left ventricular tissue from 25 cats, 18 diagnosed with HCM, including a Ragdoll cat with a homozygous MYBPC3 R820W, and 7 non-HCM cats in comparison with human HCM (from septal myectomy) and donor heart tissue. Myofibrillar protein expression was normal except that we observed 20–44% MyBP-C haploinsufficiency in 5 of the HCM cats. Troponin extracted from 8 HCM and 5 non-HCM cat hearts was incorporated into thin filaments and studied by in vitro motility assay. All HCM cat hearts had a higher (2.06 ± 0.13 fold) Ca2+-sensitivity than non-HCM cats and, in all the HCM cats, Ca2+-sensitivity was not modulated by troponin I phosphorylation. We were able to restore modulation of Ca2+-sensitivity by replacing troponin T with wild-type protein or by adding 100 μM Epigallocatechin 3-gallate (EGCG). These fundamental regulatory characteristics closely mimic those seen in human HCM indicating a common molecular mechanism that is independent of the causative mutation. Thus, the HCM cat is a potentially useful large animal model.

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“…In Maine Coon cats, for example, an MYBPC mutation (A31P) has been detected in approximately 22-42% of Maine Coon cats, while a separate MYBPC mutation (R820W) has been identified in 27% of Ragdoll cats [11]. The R820W mutation was later identified in a human family with HCM and thus represents a shared genetic etiology between cats and humans [12]. But Maine Coon cats without the A31P mutation also can develop HCM, underscoring the presence of unidentified mutations.…”

Section: Genetics Of Feline Hcmmentioning

confidence: 99%

Feline Hypertrophic Cardiomyopathy: A Spontaneous Large Animal Model of Human HCM

et al. 2017

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Hypertrophic cardiomyopathy (HCM) is a common disease in pet cats, affecting 10-15% of the pet cat population. The similarity to human HCM, the rapid progression of disease, and the defined and readily determined endpoints of feline HCM make it an excellent natural model that is genotypically and phenotypically similar to human HCM. The Maine Coon and Ragdoll cats are particularly valuable models of HCM because of myosin binding protein-C mutations and even higher disease incidence compared to the overall feline population. The cat overcomes many of the limitations of rodent HCM models, and can provide enhanced translation of information from in vitro and induced small animal models to human clinical trials. Physicians and veterinarians working together in a collaborative and interdisciplinary approach can accelerate the discovery of more effective treatments for this and other cardiovascular diseases affecting human and veterinary patients.

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The R820W mutation in the MYBPC3 gene, associated with hypertrophic cardiomyopathy in cats, causes hypertrophic cardiomyopathy and left ventricular non-compaction in humans

Cited by 38 publications

References 8 publications

The genetic basis of hypertrophic cardiomyopathy in cats and humans

The genetic basis of hypertrophic cardiomyopathy in cats and humans

Investigations into the Sarcomeric Protein and Ca2+-Regulation Abnormalities Underlying Hypertrophic Cardiomyopathy in Cats (Felix catus)

Feline Hypertrophic Cardiomyopathy: A Spontaneous Large Animal Model of Human HCM

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