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Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis.

ABSTRACT: 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.Nebulette aligns thin filaments and connects them with the myocardial Z-disk, playing a role in mechanosensation.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.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.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.

SUBMITTER: Purevjav E

PROVIDER: S-EPMC2957670 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis.

Purevjav Enkhsaikhan E Varela Jaquelin J Morgado Micaela M Kearney Debra L DL Li Hua H Taylor Michael D MD Arimura Takuro T Moncman Carole L CL McKenna William W Murphy Ross T RT Labeit Siegfried S Vatta Matteo M Bowles Neil E NE Kimura Akinori A Boriek Aladin M AM Towbin Jeffrey A JA

Journal of the American College of Cardiology 20101001 18

<h4>Objectives</h4>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.<h4>Background</h4>Nebulette aligns thin filaments and connects them with the myocardial Z-disk, playing a role in mechanosensation.<h4>Methods</h4>We generated transgenic mice with cardiac-restricted overexpression of human wild-type or mutant nebul ...[more]

PMID: 20951326

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Project description:Endocardial fibroelastosis (EFE) is a unique form of fibrosis, which forms a de novo subendocardial tissue layer encapsulating the myocardium and stunting its growth, and which is typically associated with congenital heart diseases of heterogeneous origin, such as hypoplastic left heart syndrome. Relevance of EFE was only recently highlighted through the establishment of staged biventricular repair surgery in infant patients with hypoplastic left heart syndrome, where surgical removal of EFE tissue has resulted in improvement in the restrictive physiology leading to the growth of the left ventricle in parallel with somatic growth. However, pathomechanisms underlying EFE formation are still scarce, and specific therapeutic targets are not yet known.Here, we aimed to investigate the cellular origins of EFE tissue and to gain insights into the underlying molecular mechanisms to ultimately develop novel therapeutic strategies.By utilizing a novel EFE model of heterotopic transplantation of hearts from newborn reporter mice and by analyzing human EFE tissue, we demonstrate for the first time that fibrogenic cells within EFE tissue originate from endocardial endothelial cells via aberrant endothelial to mesenchymal transition. We further demonstrate that such aberrant endothelial to mesenchymal transition involving endocardial endothelial cells is caused by dysregulated transforming growth factor beta/bone morphogenetic proteins signaling and that this imbalance is at least in part caused by aberrant promoter methylation and subsequent transcriptional suppression of bone morphogenetic proteins 5 and 7. Finally, we provide evidence that supplementation of exogenous recombinant bone morphogenetic proteins 7 effectively ameliorates endothelial to mesenchymal transition and experimental EFE in rats.In summary, our data point to aberrant endothelial to mesenchymal transition as a common denominator of infant EFE development in heterogeneous, congenital heart diseases, and to bone morphogenetic proteins 7 as an effective treatment for EFE and its restriction of heart growth.

Dataset Information

Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis.

Publications

Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis.

Similar Datasets

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