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Patients with dilated cardiomyopathy shared mutations in ANKRD1 gene
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Mutations in a gene integral for the production of cardiac ankyrin repeat protein were found in patients with dilated cardiomyopathy.
Researchers scanned DNA from 208 patients with familial or idiopathic dilated cardiomyopathy for mutations. They focused on coding region for ankyrin repeat domain 1 (ANKRD1), a transcription coinhibitor responsible for the encoding of cardiac ankyrin repeat protein (CARP).
According to the results, three missense heterozygous sequence variants (P105S, V107L and M184I) in the ANKRD1 region were located in 1.9% of patients with dilated cardiomyopathy. Mutation M184I caused a loss of binding of CARP with talin 1 and transcription cofactor FHL2. Mutation P105S also resulted in a loss of binding with talin 1.
“ANKRD1, the gene encoding CARP (a transcription cofactor with presumed stretch-based signal function), is a novel dilated cardiomyopathy gene,” the researchers wrote. “Dilated cardiomyopathy-associated variants in ANKRD1 result in dysfunction of the cellular stretch-based signaling machinery, suggesting that these are disease causing, and provide support to the hypothesis that inherited dysfunction of cardiac stretch-based signaling is present in a subset of dilated cardiomyopathy patients.”
In an accompanying editorial, Luisa Mestroni, MD, director of the molecular genetics laboratory at the University of Colorado Cardiovascular Institute in Denver, offered three potential implications for the discovery of ANKRD1 mutations, which she suggested had the potential to affect “approximately 40% of cases in hypertrophic cardiomyopathy and probably approximately 70% in dilated cardiomyopathy.
“It expands our knowledge of the mechanism leading to the hypertrophy and HF to include abnormal stretch-based signaling in response to force; this appears to be another ‘common pathway’ for hypertrophic cardiomyopathy and dilated cardiomyopathy that could be targeted by novel therapeutic strategies,” Mestroni wrote. “Although the low prevalence of mutations may currently limit routine screening for the ANKRD1 gene, we may expect that the implementation of resequencing technology will allow a systematic screening for rare cardiomyopathy genes in these patients in the near future.”
Towbin JA. J Am Coll Cardiol. 2009;54:325-333.