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Mutational spectrum of DMD mutations in dystrophinopathy patients: application of modern diagnostic techniques to a large cohort |
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| Authors: | Kevin M. Flanigan Diane M. Dunn Andrew von Niederhausern Payam Soltanzadeh Eduard Gappmaier Michael T. Howard Jacinda B. Sampson Jerry R. Mendell Cheryl Wall Wendy M. King Alan Pestronk Julaine M. Florence Anne M. Connolly Katherine D. Mathews Carrie M. Stephan Karla S. Laubenthal Brenda L. Wong Paula J. Morehart Amy Meyer Richard S. Finkel Carsten G. Bonnemann Livija Medne John W. Day Joline C. Dalton Marcia K. Margolis Veronica J. Hinton the United Dystrophinopathy Project Consortium Robert B. Weiss |
| Affiliation: | 1. Departments of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah;2. Department of Neurology, University of Utah School of Medicine, Salt Lake City, Utah;3. The Research Institute of Nationwide Children's Hospital and Ohio State University, Columbus, Ohio;4. Department of Neurology, Washington University at St. Louis, St. Louis, Missouri Department of Pathology, Washington University at St. Louis, St. Louis, Missouri;5. Department of Neurology, Washington University at St. Louis, St. Louis, Missouri;6. Department of Pediatrics, University of Iowa, Iowa City, Iowa;7. Departments of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah Department of Pediatrics, University of Iowa, Iowa City, Iowa;8. Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;9. Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;10. Department of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania Departments of Neurology and Pediatrics, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania;11. Department of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania;12. Department of Neurology, University of Minnesota, Minneapolis, Minnesota;13. Columbia–Presbyterian Hospital, New York, New York;14. Other authors (members of the UDP Consortium) are listed at the end of the article. |
| Abstract: | Mutations in the DMD gene, encoding the dystrophin protein, are responsible for the dystrophinopathies Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), and X-linked Dilated Cardiomyopathy (XLDC). Mutation analysis has traditionally been challenging, due to the large gene size (79 exons over 2.2 Mb of genomic DNA). We report a very large aggregate data set comprised of DMD mutations detected in samples from patients enrolled in the United Dystrophinopathy Project, a multicenter research consortium, and in referral samples submitted for mutation analysis with a diagnosis of dystrophinopathy. We report 1,111 mutations in the DMD gene, including 891 mutations with associated phenotypes. These results encompass 506 point mutations (including 294 nonsense mutations) and significantly expand the number of mutations associated with the dystrophinopathies, highlighting the utility of modern diagnostic techniques. Our data supports the uniform hypermutability of CGA>TGA mutations, establishes the frequency of polymorphic muscle (Dp427m) protein isoforms and reveals unique genomic haplotypes associated with “private” mutations. We note that 60% of these patients would be predicted to benefit from skipping of a single DMD exon using antisense oligonucleotide therapy, and 62% would be predicted to benefit from an inclusive multiexonskipping approach directed toward exons 45 through 55. Hum Mutat 30:1657–1666, 2009. © 2009 Wiley-Liss, Inc. |
| Keywords: | dystrophinopathy Duchenne Muscular Dystrophy DMD Becker Muscular Dystrophy BMD mutation detection |