Nesprin-2 giant safeguards nuclear envelope architecture in LMNA S143F progeria cells.

Kandert, Sebastian; Lüke, Yvonne; Kleinhenz, Tobias; Neumann, Sascha; Lu, Wenshu; Jaeger, Verena M; Munck, Martina; Wehnert, Manfred; Müller, Clemens R; Zhou, Zhongjun; Noegel, Angelika A; Dabauvalle, Marie-Christine; Karakesisoglou, Iakowos

Kandert, Sebastian; Lüke, Yvonne; Kleinhenz, Tobias; Neumann, Sascha; Lu, Wenshu; Jaeger, Verena M; Munck, Martina; Wehnert, Manfred; Müller, Clemens R; Zhou, Zhongjun; Noegel, Angelika A; Dabauvalle, Marie-Christine; Karakesisoglou, Iakowos.

Afiliación

Kandert S; Department of Cell and Developmental Biology, University of Würzburg, D97074, Würzburg, Germany.

Hum Mol Genet ; 16(23): 2944-59, 2007 Dec 01.

Article en En | MEDLINE | ID: mdl-17881656

RESUMEN

The S143F lamin A/C point mutation causes a phenotype combining features of myopathy and progeria. We demonstrate here that patient dermal fibroblast cells have dysmorphic nuclei containing numerous blebs and lobulations, which progressively accumulate as cells age in culture. The lamin A/C organization is altered, showing intranuclear and nuclear envelope (NE) aggregates and presenting often a honeycomb appearance. Immunofluorescence microscopy showed that nesprin-2 C-terminal isoforms and LAP2alpha were recovered in the cytoplasm, whereas LAP2beta and emerin were unevenly localized along the NE. In addition, the intranuclear organization of acetylated histones, histone H1 and the active form of RNA polymerase II were markedly different in patient cells. A subpopulation of mutant cells, however, expressing the 800 kDa nesprin-2 giant isoform, did not show an overt nuclear phenotype. Ectopic expression of p.S143F lamin A in fibroblasts recapitulates the patient cell phenotype, whereas no effects were observed in p.S143F LMNA keratinocytes, which highly express nesprin-2 giant. Overexpression of the mutant lamin A protein had a more severe impact on the NE of nesprin-2 giant deficient fibroblasts when compared with wild-type. In summary, our results suggest that the p.S143F lamin A mutation affects NE architecture and composition, chromatin organization, gene expression and transcription. Furthermore, our findings implicate a direct involvement of the nesprins in laminopathies and propose nesprin-2 giant as a structural reinforcer at the NE.

Asunto(s)

Lamina Tipo A/genética; Proteínas de Microfilamentos/metabolismo; Proteínas del Tejido Nervioso/metabolismo; Membrana Nuclear/metabolismo; Proteínas Nucleares/metabolismo; Progeria/genética; Progeria/metabolismo; Secuencia de Aminoácidos; Secuencia de Bases; Células Cultivadas; Cromatina/metabolismo; Cartilla de ADN/genética; Femenino; Fibroblastos/metabolismo; Fibroblastos/patología; Eliminación de Gen; Humanos; Lamina Tipo A/química; Lamina Tipo A/metabolismo; Proteínas de la Membrana/deficiencia; Proteínas de la Membrana/genética; Metaloendopeptidasas/deficiencia; Metaloendopeptidasas/genética; Proteínas de Microfilamentos/deficiencia; Proteínas de Microfilamentos/genética; Datos de Secuencia Molecular; Proteínas del Tejido Nervioso/deficiencia; Proteínas del Tejido Nervioso/genética; Membrana Nuclear/patología; Proteínas Nucleares/deficiencia; Proteínas Nucleares/genética; Fenotipo; Mutación Puntual; Progeria/patología; Homología de Secuencia de Aminoácido; Transcripción Genética

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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Progeria / Proteínas Nucleares / Lamina Tipo A / Proteínas de Microfilamentos / Proteínas del Tejido Nervioso / Membrana Nuclear Límite: Female / Humans Idioma: En Revista: Hum Mol Genet Asunto de la revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Año: 2007 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido

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