Review DMD

Review DMD - REVIEWS MECHANISMS OF DISEASE Molecular...

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The term muscular dystrophy (MD) encompasses over 30 different inherited diseases, all involving progressive weakness and degeneration of skeletal muscle (BOX 1) . MDs can be devastating diseases with weakened skele- tal muscles leading to loss of ambulation, difficulties in breathing and eating and, in most cases, premature death. Key features of dystrophic muscle include central nuclei, small regenerating fibres and accumulation of connec- tive tissue and fatty tissue (see FIG. 1 for cross-sections of normal and dystrophic muscle). MDs do not usually involve the central nervous system or peripheral nerves (although some do), despite the close anato mical rela- tionship between skeletal muscle and nerves, but they can affect the heart and other organs. Traditionally the MDs have been grouped according to their clinical and patho- logical manifestations (see Supplementary information S1 (box) for the more common types of MD). Genetically, MDs can be inherited in a dominant or recessive manner or, in many cases, caused by de novo mutations, which are therefore sporadic. As the genetic causes have become apparent, MDs have been named to reflect the defective gene, for example, ‘laminopathies’, ‘titinopathies’, ‘dystrophinopathies’ and ‘dysferlino pathies’, with the same defective gene possibly causing more than one disease phenotype; these gene- describing titles sometimes group clinically distinct diseases together. For example, mutations in the gene that encodes the giant sarcomeric protein titin can cause both tibial MD ( TMD ) and the more severe limb girdle MD ( LGMD2J ), depending on whether the patient is heterozygous for the mutation (TMD) or homozygous for the mutation (LGMD2J) 1 . Moreover, some mutated genes not only cause more than one clinically distinct MD, but can also cause diseases that do not primarily affect skeletal muscle. Mutations in the LMNA gene, which encodes the nuclear proteins lamin A and lamin C can cause MDs 2,3 as well as other diseases such as the premature ageing disease Hutchinson–Gilford progeria syndrome 4–9 . To further complicate the situation, more than one gene can produce the same MD phenotype; for example, Emery–Dreifuss MD ( EDMD ) can be caused by auto somal dominant mutations in the LMNA gene 3 or X-linked mutations in the gene encoding another nuclear protein, emerin 10 . Dystrophin was the first mutant protein shown to cause MD. Mutations of the dystrophin gene, the largest gene in the human genome, cause the most common MD, Duchenne MD ( DMD ), as well as the milder pheno type of Becker MD ( BMD ) 11 . Differing mutations within the dystrophin gene determine whether a patient shows a DMD or BMD phenotype. DMD results from an absence of dystrophin or expression of a non-functional protein, whereas BMD has been associated with reduc- tion of wild-type dystrophin or expression of a partially functional protein.
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This note was uploaded on 10/12/2010 for the course BC BC367 taught by Professor Millard during the Spring '10 term at Colby.

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Review DMD - REVIEWS MECHANISMS OF DISEASE Molecular...

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