Hypertrophic cardiomyopathy mutations in the calponin-homology domain of ACTN2 affect actin binding and cardiomyocyte Z-disc incorporation

We have discovered that two mutations at the actin binding domain (ABD) of α-actinin-2 (ACTN2), which cause hypertrophic cardiomyopathy (HCM), have minor effects on its structure and ability to bind actin and integrate into Z-discs, providing a potential disease mechanism.

• Publication year

  2016

• Venue

  Biochemical Journal

• Publication date

  2016-06-09

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1042/BCJ20160421PMID 27287556PMCID 4980809
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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• The Structure and Regulation of Human Muscle α-Actinin

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  2013cited by this paper
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  2011cited by this paper
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  2010cited by this paper
• Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: a genome-wide analysis.

  2010cited by this paper
• Z-disc genes in hypertrophic cardiomyopathy: stretching the cardiomyopathies?

  2010cited by this paper
• The vertebrate muscle Z-disc: sarcomere anchor for structure and signalling

  2009cited by this paper
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  2009cited by this paper
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  2009cited by this paper
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  2008cited by this paper
• Phaser crystallographic software

  2007cited by this paper
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  2006cited by this paper
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  2006cited by this paper
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  2006cited by this paper
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  2005cited by this paper
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  2005cited by this paper
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  2004cited by this paper
• Transmural changes in size, contractile and electrical properties of SHR left ventricular myocytes during compensated hypertrophy.

  2004cited by this paper
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  2003cited by this paper
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  2002cited by this paper
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• Correspondence e-mail:

  2000cited by this paper
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  2000cited by this paper
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  1998cited by this paper
• Free R value: cross-validation in crystallography.

  1997cited by this paper
• Refinement of macromolecular structures by the maximum-likelihood method.

  1997cited by this paper
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  1996cited by this paper
• Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults.

  1995cited by this paper
• Hypertrophic cardiomyopathy.

  1994cited by this paper
• Affinity of alpha-actinin for actin determines the structure and mechanical properties of actin filament gels.

  1993cited by this paper
• Cloning and characterization of two human skeletal muscle alpha-actinin genes located on chromosomes 1 and 11.

  1992cited by this paper
• Requirement of phosphatidylinositol 4,5-bisphosphate for alpha-actinin function.

  1992cited by this paper
• Accurate Bond and Angle Parameters for X-ray Protein Structure Refinement

  1991cited by this paper
• Impaired left ventricular relaxation in hypertrophic cardiomyopathy: relation to extent of hypertrophy.

  1990cited by this paper
• Purification of muscle actin.

  1982cited by this paper
• [18] Purification of muscle actin

  1982cited by this paper
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  1976cited by this paper

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