Brain Advance Access published online on February 14, 2006
Brain, doi:10.1093/brain/awl023
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1 Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA
* To whom correspondence should be addressed. Mutations of lamin A/C (LMNA) cause a wide range of human disorders, including progeria, lipodystrophy, neuropathies and autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD). EDMD is also caused by X-linked recessive loss-of-function mutations of emerin, another component of the inner nuclear lamina that directly interacts with LMNA. One model for disease pathogenesis of LMNA and emerin mutations is cell-specific perturbations of the mRNA transcriptome in terminally differentiated cells. To test this model, we studied 125 human muscle biopsies from 13 diagnostic groups (125 U133A, 125 U133B microarrays), including EDMD patients with LMNA and emerin mutations. A Visual and Statistical Data Analyzer (VISDA) algorithm was used to statistically model cluster hierarchy, resulting in a tree of phenotypic classifications. Validations of the diagnostic tree included permutations of U133A and U133B arrays, and use of two probe set algorithms (MAS5.0 and MBEI). This showed that the two nuclear envelope defects (EDMD LMNA, EDMD emerin) were highly related disorders and were also related to fascioscapulohumeral muscular dystrophy (FSHD). FSHD has recently been hypothesized to involve abnormal interactions of chromatin with the nuclear envelope. To identify disease-specific transcripts for EDMD, we applied a leave-one-out (LOO) cross-validation approach using LMNA patient muscle as a test data set, with reverse transcription-polymerase chain reaction (RT-PCR) validations in both LMNA and emerin patient muscle. A high proportion of top-ranked and validated transcripts were components of the same transcriptional regulatory pathway involving Rb1 and MyoD during muscle regeneration (CRI-1, CREBBP, Nap1L1, ECREBBP/p300), where each was specifically upregulated in EDMD. Using a muscle regeneration time series (27 time points) we develop a transcriptional model for downstream consequences of LMNA and emerin mutations. We propose that key interactions between the nuclear envelope and Rb and MyoD fail in EDMD at the point of myoblast exit from the cell cycle, leading to poorly coordinated phosphorylation and acetylation steps. Our data is consistent with mutations of nuclear lamina components leading to destabilization of the transcriptome in differentiated cells.
Received September 25, 2005
Revised December 23, 2005
Accepted January 11, 2006
Article
Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration
Marina Bakay 1 *,
Zuyi Wang 2 *,
Gisela Melcon 1 *,
Louis Schiltz 3,
Jianhua Xuan 4,
Po Zhao 1,
Vittorio Sartorelli 3,
Jinwook Seo 5,
Elena Pegoraro 6,
Corrado Angelini 6,
Ben Shneiderman 7,
Diana Escolar 1,
Yi-Wen Chen 1,
Sara T. Winokur 8,
Lauren M. Pachman 9,
Chenguang Fan 1,
Raul Mandler 10,
Yoram Nevo 11,
Erynn Gordon 1,
Yitan Zhu 12,
Yibin Dong 12,
Yue Wang 12,
and
Eric P. Hoffman 1 *
2 Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA; Department of Electrical Engineering and Computer Science, The Catholic University of America, Washington, DC, USA
3 Muscle Development Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, USA
4 Department of Electrical Engineering and Computer Science, The Catholic University of America, Washington, DC, USA
5 Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA; Department of Computer Science, University of Maryland, College Park, MD, USA
6 Department of Neurosciences, University of Padova, Padova, Italy
7 Department of Computer Science, University of Maryland, College Park, MD, USA
8 Department of Biological Chemistry, University of California, Irvine, CA, USA
9 Children's Memorial Research Center, Northwestern University's Feinberg School of Medicine, Chicago, IL, USA
10 Department of Neurology, George Washington University School of Medicine, Washington, DC, USA
11 Pediatric Neurology, Hadassah Medical Center, Jerusalem, Israel
12 Department of Electrical, Computer and Biomedical Engineering, Virginia Polytechnic Institute and State University, Arlington, VA, USA
Eric P. Hoffman, E-mail: ehoffman{at}cnmcresearch.org
Abstract
*These authors contributed equally to this work
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