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Human Molecular Genetics Advance Access originally published online on July 6, 2004
Human Molecular Genetics 2004 13(17):1857-1871; doi:10.1093/hmg/ddh205
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Human Molecular Genetics, Vol. 13, No. 17 © Oxford University Press 2004; all rights reserved

Localization of 4q35.2 to the nuclear periphery: is FSHD a nuclear envelope disease?

Peter S. Masny1, Ulla Bengtsson1, Seung-Ah Chung1, Jorge H. Martin1, Baziel van Engelen2, Silvere M. van der Maarel3 and Sara T. Winokur1,*

1Department of Biological Chemistry, University of California, Irvine, CA, USA, 2Department of Neurology, Nijmegen University, The Netherlands and 3Department of Human Genetics, Leiden University Medical Center, The Netherlands

Received May 18, 2004; Accepted June 29, 2004

Facioscapulohumeral muscular dystrophy (FSHD) may be a new member of the class of neuromuscular diseases (NMD) due to defects in the nuclear envelope. Unlike other NMDs with primary defects in nuclear envelope proteins, however, FSHD may result from inappropriate chromatin interactions at the envelope. 3D Immuno-FISH and a novel method of 3D by 2D analysis using NucProfile were developed to examine nuclear organization of the FSHD genomic region. In contrast to most other telomeres, the FSHD region at 4q35.2 localizes to the nuclear periphery. This localization is consistent in normal myoblasts, myotubes, fibroblasts and lymphoblasts, does not vary significantly throughout the cell cycle, and is independent of chromosome territory effects. The nuclear lamina protein lamin A/C is required for FSHD region chromatin localization to the nuclear envelope, as the association is lost in lamin A/C null fibroblasts. As both normal and affected alleles (deleted for the subtelomeric repeat D4Z4) localize to the nuclear periphery, FSHD likely arises instead from improper interactions with transcription factors or chromatin modifiers at the nuclear envelope. Interestingly, it is not D4Z4 itself that mediates interaction with the envelope, as sequences proximal to D4Z4 (i.e. D4S139) localize closer to the nuclear periphery, perhaps accounting for the chromosome 4 specificity of the disease.

* To whom correspondence should be addressed at: Department of Biological Chemistry, 202 Sprague Hall, University of California, Irvine, Irvine, CA 92697, USA. Tel: +1 9498242750; Fax: +1 9498249547; Email: stwinoku{at}uci.edu


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