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

Enkhsaikhan Purevjav, Takuro Arimura, Sibylle Augustin, Anne Cecile Huby, Ken Takagi, Shinichi Nunoda, Debra L. Kearney, Michael D. Taylor, Fumio Terasaki, Johan M. Bos, Steve R. Ommen, Hiroki Shibata, Megumi Takahashi, Manatsu Itoh-satoh, William J. Mckenna, Ross T. Murphy, Siegfried Labeit, Yoichi Yamanaka, Noboru Machida, Jeong Euy Park & 6 others Peta M.A. Alexander, Robert G. Weintraub, Yasushi Kitaura, Michael J. Ackerman, Akinori Kimura, Jeffrey Towbin

Research output: Contribution to journalArticle

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Abstract

Abnormalities in Z-disc proteins cause hypertrophic (HCM), dilated (DCM) and/or restrictive cardiomyopathy (RCM), but disease-causing mechanisms are not fully understood. Myopalladin (MYPN) is a Z-disc protein expressed in striated muscle and functions as a structural, signaling and gene expression regulating molecule in response to muscle stress. MYPN was genetically screened in 900 patients with HCM, DCM and RCM, and disease-causing mechanisms were investigated using comparative immunohistochemical analysis of the patient myocardium and neonatal rat cardiomyocytes expressing mutant MYPN. Cardiac-restricted transgenic (Tg) mice were generated and protein-protein interactions were evaluated. Two nonsense and 13 missense MYPN variants were identified in subjects with DCM, HCM and RCM with the average cardiomyopathy prevalence of 1.66%. Functional studies were performed on two variants (Q529X and Y20C) associated with variable clinical phenotypes. Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM. Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN Q529X. Cardiac-restricted MYPN Y20C Tg mice developed HCM and disrupted intercalated discs, with disturbed expression of desmin, desmoplakin, connexin43 and vinculin being evident. Failed nuclear translocation and reduced binding of Y20C-MYPN to CARP were demonstrated using in vitro and in vivo systems. MYPN mutations cause various forms of cardiomyopathy via different protein-protein interactions. Q529X-MYPN causes RCM via disturbed myofibrillogenesis, whereas Y20C-MYPN perturbs MYPN nuclear shuttling and leads to abnormal assembly of terminal Z-disc within the cardiac transitional junction and intercalated disc.

Original languageEnglish (US)
Article numberdds022
Pages (from-to)2039-2053
Number of pages15
JournalHuman molecular genetics
Volume21
Issue number9
DOIs
StatePublished - May 1 2012

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Restrictive Cardiomyopathy
Cardiomyopathies
Mutation
Ankyrin Repeat
Desmin
Muscle Development
Proteins
Cardiac Myocytes
Transgenic Mice
Desmoplakins
Vinculin
Connexin 43
Striated Muscle
Dilated Cardiomyopathy
Myocardium
Phenotype
Gene Expression
Muscles

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations. / Purevjav, Enkhsaikhan; Arimura, Takuro; Augustin, Sibylle; Huby, Anne Cecile; Takagi, Ken; Nunoda, Shinichi; Kearney, Debra L.; Taylor, Michael D.; Terasaki, Fumio; Bos, Johan M.; Ommen, Steve R.; Shibata, Hiroki; Takahashi, Megumi; Itoh-satoh, Manatsu; Mckenna, William J.; Murphy, Ross T.; Labeit, Siegfried; Yamanaka, Yoichi; Machida, Noboru; Park, Jeong Euy; Alexander, Peta M.A.; Weintraub, Robert G.; Kitaura, Yasushi; Ackerman, Michael J.; Kimura, Akinori; Towbin, Jeffrey.

In: Human molecular genetics, Vol. 21, No. 9, dds022, 01.05.2012, p. 2039-2053.

Research output: Contribution to journalArticle

Purevjav, E, Arimura, T, Augustin, S, Huby, AC, Takagi, K, Nunoda, S, Kearney, DL, Taylor, MD, Terasaki, F, Bos, JM, Ommen, SR, Shibata, H, Takahashi, M, Itoh-satoh, M, Mckenna, WJ, Murphy, RT, Labeit, S, Yamanaka, Y, Machida, N, Park, JE, Alexander, PMA, Weintraub, RG, Kitaura, Y, Ackerman, MJ, Kimura, A & Towbin, J 2012, 'Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations', Human molecular genetics, vol. 21, no. 9, dds022, pp. 2039-2053. https://doi.org/10.1093/hmg/dds022
Purevjav, Enkhsaikhan ; Arimura, Takuro ; Augustin, Sibylle ; Huby, Anne Cecile ; Takagi, Ken ; Nunoda, Shinichi ; Kearney, Debra L. ; Taylor, Michael D. ; Terasaki, Fumio ; Bos, Johan M. ; Ommen, Steve R. ; Shibata, Hiroki ; Takahashi, Megumi ; Itoh-satoh, Manatsu ; Mckenna, William J. ; Murphy, Ross T. ; Labeit, Siegfried ; Yamanaka, Yoichi ; Machida, Noboru ; Park, Jeong Euy ; Alexander, Peta M.A. ; Weintraub, Robert G. ; Kitaura, Yasushi ; Ackerman, Michael J. ; Kimura, Akinori ; Towbin, Jeffrey. / Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations. In: Human molecular genetics. 2012 ; Vol. 21, No. 9. pp. 2039-2053.
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AU - Purevjav, Enkhsaikhan

AU - Arimura, Takuro

AU - Augustin, Sibylle

AU - Huby, Anne Cecile

AU - Takagi, Ken

AU - Nunoda, Shinichi

AU - Kearney, Debra L.

AU - Taylor, Michael D.

AU - Terasaki, Fumio

AU - Bos, Johan M.

AU - Ommen, Steve R.

AU - Shibata, Hiroki

AU - Takahashi, Megumi

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AU - Mckenna, William J.

AU - Murphy, Ross T.

AU - Labeit, Siegfried

AU - Yamanaka, Yoichi

AU - Machida, Noboru

AU - Park, Jeong Euy

AU - Alexander, Peta M.A.

AU - Weintraub, Robert G.

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