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Molecular genetic and functional characterization implicate muscle-restricted coiled-coil gene (MURC) as a causal

Gabriela Rodriguez1, Tomomi Ueyama, Takehiro Ogata

  • 1Center for Cardiovascular Genetics, Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, USA.

Circulation. Cardiovascular Genetics
|June 7, 2011
PubMed

Insights

Mutations in the MURC gene are likely causes of dilated cardiomyopathy (DCM) in humans, leading to heart failure. The role of MURC mutations in hypertrophic cardiomyopathy (HCM) requires further investigation.

Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Genetic Basis of Heart Disease

Background:

  • Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are primary forms of systolic and diastolic heart failure.
  • Genetic mutations in sarcomere and cytoskeletal proteins are established causes of HCM and DCM.
  • MURC, a Z-line protein, is known to regulate cardiac function in mice.

Purpose of the Study:

  • To investigate the potential causal role of the MURC gene in human cardiomyopathies.
  • To identify and characterize mutations in MURC associated with DCM and HCM.

Main Methods:

  • Sequencing of the MURC gene in 1199 individuals (383 DCM, 307 HCM, 509 controls).
  • Segregation analysis of identified variants within families.
  • Functional studies using recombinant adenoviruses to express mutant MURC proteins in neonatal rat cardiac myocytes.

Main Results:

  • Identified 6 heterozygous DCM-specific missense variants in 8 unrelated probands.
  • Two variants (p.N128K and p.S307T) segregated with DCM inheritance.
  • A deletion variant in MURC was found in 3 HCM probands, but its segregation with HCM was uncertain.
  • Mutant MURC expression reduced RhoA activity and hypertrophic markers in cultured myocytes.

Conclusions:

  • MURC mutations likely cause loss-of-function effects and are probable causal variants in human DCM.
  • The identified DCM-associated MURC variants lead to progressive heart failure, conduction defects, and arrhythmias.
  • The causal role of a specific deletion mutation in HCM remains uncertain.
Abstract

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