A deleterious mutation in the ALMS1 gene in a naturally occurring model of hypertrophic cardiomyopathy in the Sphynx cat

Kathryn M Meurs,Sandra Tou,Darcy B Adin,Bruce W Keene,Brian G Williams,David E Malarkey,Teresa C Defrancesco,J Ashley Ezzell,Dylan Deprospero,Steven G Friedenberg

doi:10.1186/s13023-021-01740-5

Abstract

BackgroundFamilial hypertrophic cardiomyopathy is a common inherited cardiovascular disorder in people. Many causal mutations have been identified, but about 40% of cases do not have a known causative mutation. Mutations in the ALMS1 gene are associated with the development of Alstrom syndrome, a multisystem familial disease that can include cardiomyopathy (dilated, restrictive). Hypertrophic cardiomyopathy has not been described. The ALMS1 gene is a large gene that encodes for a ubiquitously expressed protein. The function of the protein is not well understood although it is believed to be associated with energy metabolism and homeostasis, cell differentiation and cell cycle control. The ALMS1 protein has also been shown to be involved in the regulation of cell cycle proliferation in perinatal cardiomyocytes. Although cardiomyocyte cell division and replication in mammals generally declines soon after birth, inhibition of ALMS1 expression in mice lead to increased cardiomyocyte proliferation, and deficiency of Alstrom protein has been suggested to impair post-natal cardiomyocyte cell cycle arrest. Here we describe the association of familial hypertrophic cardiomyopathy in Sphynx cats with a novel ALMS1 mutation.ResultsA G/C variant was identified in exon 12 (human exon 13) of the ALMS1 gene in affected cats and was positively associated with the presence of hypertrophic cardiomyopathy in the feline population (p < 0.0001). The variant was predicted to change a highly conserved nonpolar Glycine to a positively charged Arginine. This was predicted to be a deleterious change by three in silico programs. Protein prediction programs indicated that the variant changed the protein structure in this region from a coil to a helix. Light microscopy findings included myofiber disarray with interstitial fibrosis with significantly more nuclear proliferative activity in the affected cats than controls (p < 0.0001).ConclusionThis study demonstrates a novel form of cardiomyopathy associated with ALMS1 in the cat. Familial hypertrophic cardiomyopathy is a disease of genetic heterogeneity; many of the known causative genes encoding for sarcomeric proteins. Our findings suggest that variants in genes involved with cardiac development and cell regulation, like the ALMS1 gene, may deserve further consideration for association with familial hypertrophic cardiomyopathy.

Highlights

Familial hypertrophic cardiomyopathy is a common inherited cardiovascular disorder in people
This study describes the discovery of a mutation in the Alstrom syndrome protein 1 (ALMS1) gene associated with the development of familial hypertrophic cardiomyopathy in the domestic cat, an excellent model of human hypertrophic cardiomyopathy due to many similarities, including the familial nature, clinical presentation and pathologic findings [9, 10]
A G/C variant was observed in the ALMS1 gene in affected Sphynx cats at A3: 92439157 (ENSFCAG00000008756) in feline exon 12. (Fig. 1) The variant is predicted to change the amino acid from a highly conserved Glycine, a nonpolar amino acid, to a positively charged Arginine (Additional file 2: Supplemental Data Table 2). (Fig. 2) The variant was positively associated with the presence of feline hypertrophic cardiomyopathy in the cat population with a p value of < 0.0001 and was identified in 62 (27 heterozygotes, 35 homozygotes) of 71 affected Sphynx

Summary

Introduction

Familial hypertrophic cardiomyopathy is a common inherited cardiovascular disorder in people. Mutations in the ALMS1 gene are associated with the development of Alstrom syndrome, a multisystem familial disease that can include cardiomyopathy (dilated, restrictive). Meurs et al Orphanet J Rare Dis (2021) 16:108 significant number of causal mutations have been identified, in sarcomeric or sarcomeric associated genes, but it has been estimated that about 40% of cases are due to mutations in genes in which the association with cardiomyopathy has yet to be identified, genes referred to as the “missing causal genes” [2, 3] Both syndromic and nonsyndromic forms of hypertrophic cardiomyopathy exist. Mutations in the ALMS1 gene are associated with the development of Alstrom syndrome in human beings, a multisystem familial disease that can include retinal degeneration, obesity, neurosensorial deafness, type 2 diabetes and cardiomyopathy [4,5,6].

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