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Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: a genome-wide analysis

Christine Chiu1, Richard D Bagnall, Jodie Ingles

  • 1Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Newtown, Australia.

Journal of the American College of Cardiology
|December 22, 2009
PubMed

Insights

Genetic mutations in the alpha-actinin-2 (ACTN2) gene are identified as a cause of hypertrophic cardiomyopathy (HCM). This study maps the disease locus and reveals ACTN2 mutations in several HCM families, highlighting Z-disk protein gene involvement.

Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Genetic Linkage Analysis

Background:

  • Familial hypertrophic cardiomyopathy (HCM) exhibits significant genetic heterogeneity.
  • The genetic basis for HCM remains unidentified in up to 50% of cases, indicating potential novel gene involvement.

Purpose of the Study:

  • To conduct a genome-wide linkage analysis in a large family with clinically diverse hypertrophic cardiomyopathy (HCM).
  • To identify the genetic cause of HCM in this family and explore the role of Z-disk protein genes.

Main Methods:

  • Clinical assessments including history, physical examination, ECG, and echocardiography were performed on 23 family members.
  • DNA analysis involved genotyping with the AB PRISM Human Linkage mapping set and performing 2-point linkage analysis.
  • Screening for mutations in the alpha-actinin-2 (ACTN2) gene was conducted using high-resolution melt analysis.

Main Results:

  • The disease locus for HCM in this family was mapped to chromosome 1q42.2-q43.
  • A novel missense mutation, Ala119Thr, in the alpha-actinin-2 (ACTN2) gene was identified and segregated with the disease.
  • Three additional causative ACTN2 mutations (Thr495Met, Glu583Ala, Glu628Gly) were found in 4 other HCM families (1.7% of probands).

Conclusions:

  • This study provides the first genome-wide evidence that mutations in the ACTN2 gene cause hypertrophic cardiomyopathy (HCM).
  • Mutations in genes encoding Z-disk proteins represent a significant, albeit small, proportion of identified genetic causes for HCM.
Abstract

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