Human Molecular Genetics Advance Access originally published online on August 29, 2007
Human Molecular Genetics 2007 16(23):2816-2833; doi:10.1093/hmg/ddm238
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Nesprin-1 and -2 are involved in the pathogenesis of Emery–Dreifuss muscular dystrophy and are critical for nuclear envelope integrity
1 Department of Medicine and 2 Multi-Imaging Centre, Physiology Development and Neuroscience, Anatomy Building, University of Cambridge, Cambridge, UK, 3 Institute of Human Genetics, University of Greifswald, Greifswald, Germany, 4 Randall Division of Cell and Molecular Biophysics, Kings College London, London, UK, 5 Neurologische Univ.-Klinik Bergmannsheil Ruhr-Universitat Bochum, Burkle-de-la-Camp-Platz 1, D-44789 Bochum, Germany, 6 Department of Neurology, Friedrich Baur Institute, University of Munich, Ziemssentr. 1a, D-80336 Munich, Germany and 7 Division of Medical and Molecular Genetics, Kings College London, 8th Floor, Guy's Tower, Guy's Hospital, London SE1 9RT, UK
* To whom correspondence should be addressed at: Division of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation, Box 110, Addenbrooke's Hospital Hills Road, Cambridge CB2 2QQ, UK. Tel/Fax: +44 1223331504/5; Email: cs131{at}mole.bio.cam.ac.uk
Received July 5, 2007; Accepted August 21, 2007
Emery–Dreifuss muscular dystrophy (EDMD) is a heterogeneous late-onset disease involving skeletal muscle wasting and heart defects caused, in a minority of cases, by mutations in either of two genes encoding the inner nuclear membrane (INM) proteins, emerin and lamins A/C. Nesprin-1 and -2 are multi-isomeric, spectrin-repeat proteins that bind both emerin and lamins A/C and form a network in muscle linking the nucleoskeleton to the INM, the outer nuclear membrane, membraneous organelles, the sarcomere and the actin cytoskeleton. Thus, disruptions in nesprin/lamin/emerin interactions might play a role in the muscle-specific pathogenesis of EDMD. Screening for DNA variations in the genes encoding nesprin-1 (SYNE1) and nesprin-2 (SYNE2) in 190 probands with EDMD or EDMD-like phenotypes identified four heterozygous missense mutations. Fibroblasts from these patients exhibited nuclear morphology defects and specific patterns of emerin and SUN2 mislocalization. In addition, diminished nuclear envelope localization of nesprins and impaired nesprin/emerin/lamin binding interactions were common features of all EDMD patient fibroblasts. siRNA knockdown of nesprin-1 or -2 in normal fibroblasts reproduced the nuclear morphological changes and mislocalization of emerin and SUN2 observed in patient fibroblasts. Taken together, these data suggest that EDMD may be caused, in part, by uncoupling of the nucleoskeleton and cytoskeleton because of perturbed nesprin/emerin/lamin interactions.
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