Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis

Enkhsaikhan Purevjav, Jaquelin Varela, Micaela Morgado, Debra L. Kearney, Hua Li, Michael D. Taylor, Takuro Arimura, Carole L. Moncman, William McKenna, Ross T. Murphy, Siegfried Labeit, Matteo Vatta, Neil E. Bowles, Akinori Kimura, Aladin M. Boriek, Jeffrey Towbin

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Objectives Four variants (K60N, Q128R, G202R, and A592E) in the nebulette gene were identified in patients with dilated cardiomyopathy (DCM) and endocardial fibroelastosis. We sought to determine if these mutations are cardiomyopathy causing. Background Nebulette aligns thin filaments and connects them with the myocardial Z-disk, playing a role in mechanosensation. Methods We generated transgenic mice with cardiac-restricted overexpression of human wild-type or mutant nebulette. Chimera and transgenic mice were examined at 4, 6, and 12 months of age by echocardiography and cardiac magnetic resonance imaging. The hearts from embryos and adult mice were assessed by histopathologic, immunohistochemical, ultrastructural, and protein analyses. Rat H9C2 cardiomyoblasts with transient expression of nebulette underwent cyclic mechanical strain. Results We identified lethal cardiac structural abnormalities in mutant embryonic hearts (K60N and Q128R). Founders of the mutant mouse lines developed DCM with severe heart failure. An irregular localization pattern for nebulette and impaired desmin expression were noted in the proband and chimeric Q128R mice. Mutant G202R and A592E mice exhibited left ventricular dilation and impaired function with specific changes in I-band and Z-disk proteins by 6 months of age. The mutations modulated distribution of nebulette in the sarcomere and Z-disk during stretch of H9C2 cells. Conclusions Nebulette is a new susceptibility gene for endocardial fibroelastosis and DCM. Different mutations in nebulette trigger specific mechanisms, converging to a common pathological cascade leading to endocardial fibroelastosis and DCM.

Original languageEnglish (US)
Pages (from-to)1493-1502
Number of pages10
JournalJournal of the American College of Cardiology
Volume56
Issue number18
DOIs
StatePublished - Oct 26 2010
Externally publishedYes

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Endocardial Fibroelastosis
Dilated Cardiomyopathy
Mutation
Transgenic Mice
Sarcomeres
Desmin
Cardiomyopathies
Genes
Echocardiography
Dilatation
Embryonic Structures
Heart Failure
Magnetic Resonance Imaging
Proteins

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis. / Purevjav, Enkhsaikhan; Varela, Jaquelin; Morgado, Micaela; Kearney, Debra L.; Li, Hua; Taylor, Michael D.; Arimura, Takuro; Moncman, Carole L.; McKenna, William; Murphy, Ross T.; Labeit, Siegfried; Vatta, Matteo; Bowles, Neil E.; Kimura, Akinori; Boriek, Aladin M.; Towbin, Jeffrey.

In: Journal of the American College of Cardiology, Vol. 56, No. 18, 26.10.2010, p. 1493-1502.

Research output: Contribution to journalArticle

Purevjav, E, Varela, J, Morgado, M, Kearney, DL, Li, H, Taylor, MD, Arimura, T, Moncman, CL, McKenna, W, Murphy, RT, Labeit, S, Vatta, M, Bowles, NE, Kimura, A, Boriek, AM & Towbin, J 2010, 'Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis', Journal of the American College of Cardiology, vol. 56, no. 18, pp. 1493-1502. https://doi.org/10.1016/j.jacc.2010.05.045
Purevjav, Enkhsaikhan ; Varela, Jaquelin ; Morgado, Micaela ; Kearney, Debra L. ; Li, Hua ; Taylor, Michael D. ; Arimura, Takuro ; Moncman, Carole L. ; McKenna, William ; Murphy, Ross T. ; Labeit, Siegfried ; Vatta, Matteo ; Bowles, Neil E. ; Kimura, Akinori ; Boriek, Aladin M. ; Towbin, Jeffrey. / Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis. In: Journal of the American College of Cardiology. 2010 ; Vol. 56, No. 18. pp. 1493-1502.
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abstract = "Objectives Four variants (K60N, Q128R, G202R, and A592E) in the nebulette gene were identified in patients with dilated cardiomyopathy (DCM) and endocardial fibroelastosis. We sought to determine if these mutations are cardiomyopathy causing. Background Nebulette aligns thin filaments and connects them with the myocardial Z-disk, playing a role in mechanosensation. Methods We generated transgenic mice with cardiac-restricted overexpression of human wild-type or mutant nebulette. Chimera and transgenic mice were examined at 4, 6, and 12 months of age by echocardiography and cardiac magnetic resonance imaging. The hearts from embryos and adult mice were assessed by histopathologic, immunohistochemical, ultrastructural, and protein analyses. Rat H9C2 cardiomyoblasts with transient expression of nebulette underwent cyclic mechanical strain. Results We identified lethal cardiac structural abnormalities in mutant embryonic hearts (K60N and Q128R). Founders of the mutant mouse lines developed DCM with severe heart failure. An irregular localization pattern for nebulette and impaired desmin expression were noted in the proband and chimeric Q128R mice. Mutant G202R and A592E mice exhibited left ventricular dilation and impaired function with specific changes in I-band and Z-disk proteins by 6 months of age. The mutations modulated distribution of nebulette in the sarcomere and Z-disk during stretch of H9C2 cells. Conclusions Nebulette is a new susceptibility gene for endocardial fibroelastosis and DCM. Different mutations in nebulette trigger specific mechanisms, converging to a common pathological cascade leading to endocardial fibroelastosis and DCM.",
author = "Enkhsaikhan Purevjav and Jaquelin Varela and Micaela Morgado and Kearney, {Debra L.} and Hua Li and Taylor, {Michael D.} and Takuro Arimura and Moncman, {Carole L.} and William McKenna and Murphy, {Ross T.} and Siegfried Labeit and Matteo Vatta and Bowles, {Neil E.} and Akinori Kimura and Boriek, {Aladin M.} and Jeffrey Towbin",
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T1 - Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis

AU - Purevjav, Enkhsaikhan

AU - Varela, Jaquelin

AU - Morgado, Micaela

AU - Kearney, Debra L.

AU - Li, Hua

AU - Taylor, Michael D.

AU - Arimura, Takuro

AU - Moncman, Carole L.

AU - McKenna, William

AU - Murphy, Ross T.

AU - Labeit, Siegfried

AU - Vatta, Matteo

AU - Bowles, Neil E.

AU - Kimura, Akinori

AU - Boriek, Aladin M.

AU - Towbin, Jeffrey

PY - 2010/10/26

Y1 - 2010/10/26

N2 - Objectives Four variants (K60N, Q128R, G202R, and A592E) in the nebulette gene were identified in patients with dilated cardiomyopathy (DCM) and endocardial fibroelastosis. We sought to determine if these mutations are cardiomyopathy causing. Background Nebulette aligns thin filaments and connects them with the myocardial Z-disk, playing a role in mechanosensation. Methods We generated transgenic mice with cardiac-restricted overexpression of human wild-type or mutant nebulette. Chimera and transgenic mice were examined at 4, 6, and 12 months of age by echocardiography and cardiac magnetic resonance imaging. The hearts from embryos and adult mice were assessed by histopathologic, immunohistochemical, ultrastructural, and protein analyses. Rat H9C2 cardiomyoblasts with transient expression of nebulette underwent cyclic mechanical strain. Results We identified lethal cardiac structural abnormalities in mutant embryonic hearts (K60N and Q128R). Founders of the mutant mouse lines developed DCM with severe heart failure. An irregular localization pattern for nebulette and impaired desmin expression were noted in the proband and chimeric Q128R mice. Mutant G202R and A592E mice exhibited left ventricular dilation and impaired function with specific changes in I-band and Z-disk proteins by 6 months of age. The mutations modulated distribution of nebulette in the sarcomere and Z-disk during stretch of H9C2 cells. Conclusions Nebulette is a new susceptibility gene for endocardial fibroelastosis and DCM. Different mutations in nebulette trigger specific mechanisms, converging to a common pathological cascade leading to endocardial fibroelastosis and DCM.

AB - Objectives Four variants (K60N, Q128R, G202R, and A592E) in the nebulette gene were identified in patients with dilated cardiomyopathy (DCM) and endocardial fibroelastosis. We sought to determine if these mutations are cardiomyopathy causing. Background Nebulette aligns thin filaments and connects them with the myocardial Z-disk, playing a role in mechanosensation. Methods We generated transgenic mice with cardiac-restricted overexpression of human wild-type or mutant nebulette. Chimera and transgenic mice were examined at 4, 6, and 12 months of age by echocardiography and cardiac magnetic resonance imaging. The hearts from embryos and adult mice were assessed by histopathologic, immunohistochemical, ultrastructural, and protein analyses. Rat H9C2 cardiomyoblasts with transient expression of nebulette underwent cyclic mechanical strain. Results We identified lethal cardiac structural abnormalities in mutant embryonic hearts (K60N and Q128R). Founders of the mutant mouse lines developed DCM with severe heart failure. An irregular localization pattern for nebulette and impaired desmin expression were noted in the proband and chimeric Q128R mice. Mutant G202R and A592E mice exhibited left ventricular dilation and impaired function with specific changes in I-band and Z-disk proteins by 6 months of age. The mutations modulated distribution of nebulette in the sarcomere and Z-disk during stretch of H9C2 cells. Conclusions Nebulette is a new susceptibility gene for endocardial fibroelastosis and DCM. Different mutations in nebulette trigger specific mechanisms, converging to a common pathological cascade leading to endocardial fibroelastosis and DCM.

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