Human Molecular Genetics Advance Access originally published online on September 19, 2007
Human Molecular Genetics 2007 16(23):2944-2959; doi:10.1093/hmg/ddm255
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Nesprin-2 giant safeguards nuclear envelope architecture in LMNA S143F progeria cells
1 Department of Cell and Developmental Biology, University of Würzburg, D97074 Würzburg, Germany, 2 Department of Human Genetics, University of Würzburg, Germany, 3 Center for Biochemistry, Medical Faculty, 4 Center for Molecular Medicine, University of Cologne, 50931 Cologne, Germany, 5 Ernst-Moritz-Arndt-University, Institute of Human Genetics, 17487 Greifswald, Germany, 6 Department of Biochemistry, University of Hong Kong, 21 Sassoon Road, Hong Kong and 7 Department of Biological Sciences, The School of Biological and Biomedical Sciences, The University of Durham, Durham, UK
* To whom correspondence should be addressed at: Center for Biochemistry, Medical Faculty, University of Cologne, Joseph-Stelzmann-Street 52, D-50931 Cologne, Germany. Tel: +49 2214786987; Fax: +49 2214786979; E-mail: iakowos.karakesisoglou{at}uni-koeln.de (I. Karakesisoglou). Department of Cell and Developmental Biology, University of Würzburg, Am Hubland, D97074 Würzburg, Germany. Tel: +49 9318884273; Fax: +49 9318884252; E-mail: mcd{at}biozentrum.uni-wuerzburg.de (Marie-Christine Dabauvalle)
Received May 15, 2007; Accepted September 2, 2007
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 LAP2
were recovered in the cytoplasm, whereas LAP2ß 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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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