Brain Advance Access originally published online on February 14, 2006
Brain 2006 129(4):996-1013; doi:10.1093/brain/awl023
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Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb–MyoD pathways in muscle regeneration
1 Research Center for Genetic Medicine, Children's National Medical Center, 2 Department of Electrical Engineering and Computer Science, The Catholic University of America, 3 Department of Neurology, George Washington University School of Medicine, Washington, DC, 4 Muscle Development Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, 5 Department of Computer Science, University of Maryland, College Park, MD, 6 Department of Biological Chemistry, University of California, Irvine, CA, 7 Children's Memorial Research Center, Northwestern University's Feinberg School of Medicine, Chicago, IL, 8 Department of Electrical, Computer and Biomedical Engineering, Virginia Polytechnic Institute and State University, Arlington, VA, USA, 9 Department of Neurosciences, University of Padova, Padova, Italy and 10 Pediatric Neurology, Hadassah Medical Center, Jerusalem, Israel
Correspondence to: Dr Eric Hoffman, PhD, Director, Research Center for Genetic Medicine, Children's National Medical Center, 111 Michigan Ave NW, Washington DC 20010, USA E-mail: ehoffman{at}cnmcresearch.org
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.
Key Words: Skeletal muscle; lamin A/C; emerin; Emery-Dreifuss muscular dystrophy
Abbreviations: EDMD = Emery–Dreifuss muscular dystrophy; FSHD = fascioscapulohumeral muscular dystrophy; IDG = individual discriminatory genes; JDG = jointly discriminatory genes; LGMD = limb-girdle muscular dystrophy; LOO = leave-one-out; RT–PCR = reverse transcription–polymerase chain reaction; VISDA = Visual and Statistical Data Analyzer; wFC = weighted Fisher criterion
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Received September 25, 2005. Revised December 23, 2005. Accepted January 11, 2006.
* These authors contributed equally to this work
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