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Published on: August 8, 2022
Cardiac ankyrin repeat protein gene (ANKRD1) mutations in hypertrophic cardiomyopathy
Takuro Arimura1, J Martijn Bos, Akinori Sato
1Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. akitis@mri.tmd.ac.jp
Insights
New hypertrophic cardiomyopathy (HCM) genes were identified. Mutations in the ankyrin repeat domain 1 (ANKRD1) gene, encoding cardiac ankyrin repeat protein (CARP), were linked to abnormal CARP localization and HCM pathogenesis.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
Background:
- Hypertrophic cardiomyopathy (HCM) is often caused by mutations in sarcomeric protein genes, yet causative mutations remain unidentified in about half of patients.
- The ankyrin repeat domain 1 (ANKRD1) gene, encoding cardiac ankyrin repeat protein (CARP), a Z-disc component, was investigated as a potential novel HCM-susceptibility gene.
Purpose of the Study:
- To identify novel disease genes for hypertrophic cardiomyopathy (HCM).
- To investigate the functional consequences of mutations in the ANKRD1 gene and its interaction with other sarcomeric proteins.
Main Methods:
- Genetic analysis of 384 HCM patients for mutations in ANKRD1 and TTN (titin/connectin).
- Coimmunoprecipitation assays to assess protein interactions.
- Functional studies in neonatal rat cardiomyocytes to evaluate the impact of ANKRD1 mutations.
Main Results:
- Three ANKRD1 missense mutations (Pro52Ala, Thr123Met, Ile280Val) were identified in HCM patients.
- These ANKRD1 mutations enhanced the binding of CARP to titin/connectin and myopalladin.
- Mutations in TTN's N2A domain also affected CARP binding, and ANKRD1 mutations led to abnormal CARP localization in cardiomyocytes.
Conclusions:
- Abnormalities in cardiac ankyrin repeat protein (CARP), potentially due to ANKRD1 gene mutations, may contribute to the development of hypertrophic cardiomyopathy (HCM).
Objectives:
The purpose of this study was to explore a novel disease gene for hypertrophic cardiomyopathy (HCM) and to evaluate functional alterations caused by mutations.
Background:
Mutations in genes encoding myofilaments or Z-disc proteins of the cardiac sarcomere cause HCM, but the disease-causing mutations can be found in one-half of the patients, indicating that novel HCM-susceptibility genes await discovery. We studied a candidate gene, ankyrin repeat domain 1 (ANKRD1), encoding for the cardiac ankyrin repeat protein (CARP) that is a Z-disc component interacting with N2A domain of titin/connectin and N-terminal domain of myopalladin.
Methods:
We analyzed 384 HCM patients for mutations in ANKRD1 and in the N2A domain of titin/connectin gene (TTN). Interaction of CARP with titin/connectin or myopalladin was investigated using coimmunoprecipitation assay to demonstrate the functional alteration caused by ANKRD1 or TTN mutations. Functional abnormalities caused by the ANKRD1 mutations were also examined at the cellular level in neonatal rat cardiomyocytes.
Results:
Three ANKRD1 missense mutations, Pro52Ala, Thr123Met, and Ile280Val, were found in 3 patients. All mutations increased binding of CARP to both titin/connectin and myopalladin. In addition, TTN mutations, Arg8500His, and Arg8604Gln in the N2A domain were found in 2 patients, and these mutations increased binding of titin/connectin to CARP. Myc-tagged CARP showed that the mutations resulted in abnormal localization of CARP in cardiomyocytes.
Conclusions:
CARP abnormalities may be involved in the pathogenesis of HCM.
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