Kathryn M Meurs1, Brian G Williams2, Dylan DeProspero2, Steven G Friedenberg3, David E Malarkey4, J Ashley Ezzell5, Bruce W Keene2, Darcy B Adin2, Teresa C DeFrancesco2, Sandra Tou2. 1. Department of Veterinary Clinical Sciences, North Carolina State University, Raleigh, NC, 27607, USA. kate_meurs@ncsu.edu. 2. Department of Veterinary Clinical Sciences, North Carolina State University, Raleigh, NC, 27607, USA. 3. Department of Veterinary Clinical Sciences, University of Minnesota, Saint Paul, MN, 55108, USA. 4. National Toxicology Program Pathology Group, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, 27709, USA. 5. Histology Research Core Facility, Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, 27599, USA.
Abstract
BACKGROUND: Familial 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. RESULTS: A 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). CONCLUSION: This 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.
BACKGROUND: Familial 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. RESULTS: A 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). CONCLUSION: This 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.
Authors: S T Sherry; M H Ward; M Kholodov; J Baker; L Phan; E M Smigielski; K Sirotkin Journal: Nucleic Acids Res Date: 2001-01-01 Impact factor: 16.971
Authors: Tom Hearn; Glenn L Renforth; Cosma Spalluto; Neil A Hanley; Karen Piper; Sarah Brickwood; Chris White; Vincent Connolly; James F N Taylor; Isabelle Russell-Eggitt; Dominque Bonneau; Mark Walker; David I Wilson Journal: Nat Genet Date: 2002-04-08 Impact factor: 38.330
Authors: Kathryn M Meurs; Ximena Sanchez; Ryan M David; Neil E Bowles; Jeffrey A Towbin; Peter J Reiser; Judith A Kittleson; Marcia J Munro; Keith Dryburgh; Kristin A Macdonald; Mark D Kittleson Journal: Hum Mol Genet Date: 2005-10-19 Impact factor: 6.150