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Human Molecular Genetics Advance Access published online on August 29, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm238
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Nesprin-1 and -2 are involved in the pathogenesis of Emery-Dreifuss Muscular Dystrophy and are critical for nuclear envelope integrity

Qiuping Zhang1, Cornelia Bethmann2, Nathalie F. Worth1, John D. Davies1, Christina Wasner2, Anja Feuer2, Cassandra D. Ragnauth1, Qijian Yi1, Jason A. Mellad1, Derek T. Warren1, Matthew A. Wheeler3, Juliet A. Ellis3, Jeremy N. Skepper4, Matthias Vorgerd5, Beate Schlotter-Weigel6, Peter L. Weissberg1, Roland G. Roberts7, Manfred Wehnert2 and Catherine M. Shanahan1,*

1 Department of Medicine, University of Cambridge, Cambridge, UK 2 Institute of Human Genetics, University of Greifswald, Greifswald, Germany 3 Randall Division of Cell and Molecular Biophysics, Kings College London, London, UK 4 Multi-Imaging Centre, Physiology Development and Neuroscience, Anatomy Building, University of Cambridge, Cambridge, UK 5 Neurologische Univ.-Klinik Bergmannsheil Ruhr-Universitat Bochum, Burkle-de-la-Camp-Platz 1, D-44789 Bochum, Germany 6 Friedrich Baur Institute, Department of Neurology, University of Munich, Ziemssentr. 1a, D-80336 Munich, Germany 7 Division of Medical and Molecular Genetics, GKT Medical School, 8th Floor, Guy's Tower, Guy's Hospital, London SE1 9RT, UK

* Address for Correspondence: Dr. Catherine M. Shanahan, Division of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation, Box 110, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, UK. Phone/FAX: 44-1223-331504/5, Email: cs131{at}mole.bio.cam.ac.uk

Received July 5, 2007; Revised August 21, 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 (ONM), 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 mislocalisation. In addition, diminished nuclear envelope (NE) localisation of nesprins and impaired nesprin/emerin/lamin binding interactions were a common feature of all EDMD patient fibroblasts. siRNA knockdown of nesprin-1 or -2 in normal fibroblasts reproduced the nuclear morphological changes and mislocalisation of emerin and SUN2 observed in patient fibroblasts. Taken together this data suggests that EDMD may be caused, in part, by uncoupling of the nucleoskeleton and cytoskeleton due to perturbed nesprin/emerin/lamin interactions.


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