Prevalence of the MYBPC3-A31P mutation in a large European feline population and association with hypertrophic cardiomyopathy in the Maine Coon breed

Mary, J.; Chetboul, Valérie; Sampedrano, Carolina Carlos; Abitbol, Marie; Gouni, Vassiliki; Tréhiou-Sechi, Emilie; Tissier, Renaud; Queney, Guillaume; Pouchelon, Jean‐Louis; Thomas, Anne

doi:10.1016/j.jvc.2010.06.004

Cited by 39 publications

(59 citation statements)

References 30 publications

(32 reference statements)

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“…It might be assumed that a pure breed domestic animal with a familial mutation would have less genetic heterogeneity than the diverse population of human beings. However, other examples of cardiomyopathy in domestic animals have refuted this assumption, including familial hypertrophic cardiomyopathy in the Maine Coon cat, where there are at least two separate mutations (Mary et al 2010).…”

Section: Discussionmentioning

confidence: 99%

A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomyopathy in the Doberman pinscher

et al. 2012

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Familial dilated cardiomyopathy is a primary myocardial disease that can result in the development of congestive heart failure and sudden cardiac death. Spontaneous animal models of familial dilated cardiomyopathy exist and the Doberman pinscher dog is one of the most commonly reported canine breeds. The objective of this study was to evaluate familial dilated cardiomyopathy in the Doberman pinscher dog using a genome-wide association study for a genetic alteration(s) associated with the development of this disease in this canine model. Genome-wide association analysis identified an area of statistical significance on canine chromosome 14 (p(raw) = 9.999e-05 corrected for genome-wide significance), fine-mapping of additional SNPs flanking this region localized a signal to 23,774,190-23,781,919 (p = 0.001) and DNA sequencing identified a 16-base pair deletion in the 5' donor splice site of intron 10 of the pyruvate dehydrogenase kinase 4 gene in affected dogs (p < 0.0001). Electron microscopy of myocardium from affected dogs demonstrated disorganization of the Z line, mild to moderate T tubule and sarcoplasmic reticulum dilation, marked pleomorphic mitochondrial alterations with megamitochondria, scattered mitochondria with whorling and vacuolization and mild aggregates of lipofuscin granules. In conclusion, we report the identification of a splice site deletion in the PDK4 gene that is associated with the development of familial dilated cardiomyopathy in the Doberman pinscher dog.

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Section: Discussionmentioning

confidence: 99%

A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomyopathy in the Doberman pinscher

et al. 2012

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“…In the present study, a test was performed to determine whether the same mutation was responsible, as has been described for Maine Coon cats, but the results were negative. This was expected because the MYBPC3 mutation A31P seems to be specific to that breed (MARY et al, 2010). Moreover, some authors have suggested that this mutation is not the only cause of HCM in cats (KITTLESON et al, 2010).…”

Section: Discussionmentioning

confidence: 96%

Identification of the presence of the mutation of the gene of PKD not associated with mutation of MYBPC3-A31P of HCM in Persian cats – Case Report

et al. 2015

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Polycystic kidney disease (PKD) is a hereditary autosomal dominant disorder that mainly affects Persian cats; it is an important cause of chronic kidney disease in this species. Hypertrophic cardiomyopathy (HCM) is the most common heart disease in cats, and there is evidence of a genetic origin in some breeds. Although neither of these disorders is rare in cats, according to our literature review, this is the first report of the concomitant occurrence of PKD and HCM in Persian cats in Brazil. Key words: Feline, PKD, HCM, Persian ResumoA doença renal policística (PKD) é uma doença hereditária autossômica dominante que acomete principalmente gatos da raça Persa sendo importante causa de doença renal crônica nesta espécie. A miocardiopatia hipertrófica (CMH) é a doença cardíaca mais comum de gatos, com evidência de origem genética em algumas raças. Apesar de serem doenças frequentemente descritas em gatos, segundo a literatura revisada, este é o primeiro relato da ocorrência concomitante de PKD e CMH em gatos da raça Persa no Brasil.

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“…The finding that the A31P mutant protein makes up only a small percentage of the total pool of cMyBP-C in cats heterozygous for the mutation provides an explanation for why heterozygous A31P cats are mostly unaffected whereas A31P homozygous cats are at elevated risk for HCM in the general cat population [15-17]. That is, heterozygous cats have near normal amounts of wild-type cMyBP-C (Figure 4A,B) and express only a small amount of A31P mutant cMyBP-C (Figure 4E,F), which is apparently not sufficient to significantly elevate risk for HCM.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it is only when the entire cellular pool of cMyBP-C consists of the mutant A31P protein that homozygous cats are at increased risk for HCM. However, the susceptibility of A31P homozygous cats to HCM [15-17] contrasts with the more typical autosomal dominant pattern of inheritance for HCM mutations in human patients where inheritance of a single variant allele (heterozygous genotype) is generally sufficient to cause disease [3]. Homozygous inheritance of the A31P substitution in cats may be more similar to homozygous inheritance of mutant alleles or compound inheritance patterns in people where gene dosage effects have been reported with disease being more severe or occurring with an earlier onset in homozygous patients or in patients that carry 2 or more sequence variants in different genes [3, 38].…”

Section: Discussionmentioning

confidence: 99%

“…HCM is the most common cause of heart failure in cats and, similar to HCM in people, is characterized by abnormal regional or global thickening of the left ventricle, left ventricle outflow tract obstruction including systolic anterior motion of the mitral valve (SAM), and sudden cardiac death [12-14]. Since its original description, the A31P allele has been identified with high frequency in outbred Maine Coon cat populations throughout the world where homozygous inheritance of the A31P allele is associated with an increased odds ratio for HCM in cats [15-17]. Because inheritance of the A31P allele was associated with reduced cMyBP-C protein in the original report of this mutation [11], we sought to determine whether cMyBP-C protein structure was altered by the A31P mutation, whether the A31P mutation affects localization of cMyBP-C within the sarcomere, and to quantify cMyBP-C expression in a larger population of cats heterozygous and homozygous for the A31P allele.…”

Section: Introductionmentioning

confidence: 99%

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The A31P missense mutation in cardiac myosin binding protein C alters protein structure but does not cause haploinsufficiency

Dijk

Kooiker

Mazzalupo

et al. 2016

Archives of Biochemistry and Biophysics

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Mutations in MYBPC3, the gene encoding cardiac myosin binding protein C (cMyBP-C), are a major cause of hypertrophic cardiomyopathy (HCM). While most mutations encode premature stop codons, missense mutations causing single amino acid substitutions are also common. Here we investigated effects of a single proline for alanine substitution at amino acid 31 (A31P) in the C0 domain of cMyBP-C, which was identified as a natural cause of HCM in cats. Results using recombinant proteins showed that the mutation disrupted C0 structure, altered sensitivity to trypsin digestion, and reduced recognition by an antibody that preferentially recognizes N-terminal domains of cMyBP-C. Western blots detecting A31P cMyBP-C in myocardium of cats heterozygous for the mutation showed a reduced amount of A31P mutant protein relative to wild-type cMyBP-C, but the total amount of cMyBP-C was not different in myocardium from cats with or without the A31P mutation indicating altered rates of synthesis/degradation of A31P cMyBP-C. Also, the mutant A31P cMyBP-C was properly localized in cardiac sarcomeres. These results indicate that reduced protein expression (haploinsufficiency) cannot account for effects of the A31P cMyBP-C mutation and instead suggest that the A31P mutation causes HCM through a poison polypeptide mechanism that disrupts cMyBP-C or myocyte function.

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Prevalence of the MYBPC3-A31P mutation in a large European feline population and association with hypertrophic cardiomyopathy in the Maine Coon breed

Cited by 39 publications

References 30 publications

A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomyopathy in the Doberman pinscher

A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomyopathy in the Doberman pinscher

Identification of the presence of the mutation of the gene of PKD not associated with mutation of MYBPC3-A31P of HCM in Persian cats – Case Report

The A31P missense mutation in cardiac myosin binding protein C alters protein structure but does not cause haploinsufficiency

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