Journal Article

Nesprin-2 giant safeguards nuclear envelope architecture in <i>LMNA</i> S143F progeria cells

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

in Human Molecular Genetics

Volume 16, issue 23, pages 2944-2959
Published in print December 2007 | ISSN: 0964-6906
Published online September 2007 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddm255
Nesprin-2 giant safeguards nuclear envelope architecture in LMNA S143F progeria cells

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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 LAP2α were recovered in the cytoplasm, whereas LAP2β 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.

Journal Article.  9986 words.  Illustrated.

Subjects: Genetics and Genomics

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