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Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations

Enkhsaikhan Purevjav1, Takuro Arimura, Sibylle Augustin

  • 1The Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.

Human Molecular Genetics
|January 31, 2012
PubMed

Insights

Mutations in the Z-disc protein myopalladin (MYPN) cause various cardiomyopathies, including hypertrophic, dilated, and restrictive forms. These MYPN variants disrupt muscle structure and function through distinct molecular mechanisms.

Area of Science:

  • Cardiovascular Biology
  • Molecular Genetics
  • Muscle Physiology

Background:

  • Z-disc protein abnormalities are linked to cardiomyopathies (HCM, DCM, RCM).
  • The precise disease mechanisms remain incompletely understood.
  • Myopalladin (MYPN) is a Z-disc protein crucial for striated muscle structure, signaling, and gene regulation under stress.

Purpose of the Study:

  • To genetically screen patients for MYPN variants associated with cardiomyopathy.
  • To investigate the disease-causing mechanisms of identified MYPN variants.
  • To elucidate how MYPN mutations lead to different forms of cardiomyopathy.

Main Methods:

  • Genetic screening of 900 patients with HCM, DCM, and RCM.
  • Immunohistochemical analysis of patient myocardium and engineered rat cardiomyocytes.
  • Generation of cardiac-restricted transgenic (Tg) mice expressing MYPN variants.
  • In vitro and in vivo studies of protein-protein interactions and cellular localization.

Main Results:

  • Identified 15 MYPN variants (2 nonsense, 13 missense) in 1.66% of patients.
  • The Y20C-MYPN variant was associated with HCM or DCM, while Q529X-MYPN was linked to familial RCM.
  • MYPN(Q529X) disrupted myofibrillogenesis and key Z-disc proteins (α-actinin2, desmin, CARP).
  • MYPN(Y20C) Tg mice showed HCM, disrupted intercalated discs, and altered expression of desmin, desmoplakin, connexin43, and vinculin.
  • Y20C-MYPN exhibited failed nuclear translocation and reduced CARP binding.

Conclusions:

  • MYPN mutations are a cause of diverse cardiomyopathies through distinct mechanisms.
  • Q529X-MYPN induces RCM by impairing myofibrillogenesis.
  • Y20C-MYPN leads to HCM/DCM by disrupting MYPN nuclear transport and Z-disc assembly.

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