Very mild muscular dystrophy associated with the deletion of 46% of dystrophin

• Published in: Nature (London) 1990-01, Vol.343 (6254), p.180-182
• Main Authors: England, S. B, Nicholson, L. V. B, Johnson, M. A, Forrest, S. M, Love, D. R, Zubrzycka-Gaarn, E. E, Bulman, D. E, Harris, J. B, Davies, K.E
• Format: Article
• Language: English
• Subjects: Age; Base pairs; Becker's muscular dystrophy; Biological and medical sciences; Biopsy; Blotting, Western; Bone mineral density; Chromosome Deletion; Clonal deletion; Deoxyribonucleic acid; Diseases of striated muscles. Neuromuscular diseases; DNA; Duchenne's muscular dystrophy; Dystrophin; Dystrophy; Exons; Female; Gene deletion; Gene therapy; Genes; Genomics; Humanities and Social Sciences; Humans; Immunoblotting; Immunology; letter; Low level; Male; Medical research; Medical sciences; Middle Aged; multidisciplinary; Muscle Proteins - analysis; Muscle Proteins - genetics; Muscles; Muscles - metabolism; Muscles - pathology; Muscular Dystrophies - genetics; Muscular Dystrophies - pathology; Muscular Dystrophies - physiopathology; Muscular dystrophy; Mutation; Neurology; Nucleic Acid Hybridization; Nucleotide sequence; Patients; Pedigree; Phenotypes; Polypeptides; Protein Conformation; Proteins; Reference Values; Restriction Mapping; Science; Science (multidisciplinary); Transcription
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/343180a0

DUCHENNE muscular dystrophy (DMD) 1 and Becker muscular dystrophy (BMD), a much milder form of the disease where the age of onset can sometimes be as late as the third or fourth decade of life, are caused by mutations in the same X-linked gene 2–7 , a 14 kilobase (kb) transcript 6,7 which is spread over more than 2 megabases of the human X chromosome 8–10. The corresponding protein, dystrophin, has a relative molecular mass of 400,000 (ref. 11). Most mutations causing DMD and BMD are deleá-tions 7,12,13 (reviewed in ref. 14) and deletions associated with both phenotypes are observed throughout the gene sequence. This observation led to the suggestion 15 that DMD patients possess deletions that disrupt the reading frame of the protein, whereas BMD patients have deletions that retain the translational reading frame and enable the muscle cells to produce altered dystrophin products. This theory is supported by immunoblotting studies, which show that DMD patients lack dystrophin in their muscle cells or that dystrophin is present at very low levels, whereas BMD patients produce a protein with reduced abundance or abnormal size 16 . Here we describe a deletion of the dystrophin gene in a family segregating for very mild BMD, one member of which was still ambulant at age 61 years, which removes a central part of the dystrophin gene encompassing 5,106 base pairs of coding sequence, almost half the coding information. Immunological analysis of muscle from one of the patients demonstrates that this mutation results in the production of a truncated polypeptide localized correctly in the muscle cell. These results are particularly significant in the context of gene therapy which, if it is ever envisaged, would be facilitated by the replacement of the very large dystrophin gene with a more manipulatable mini-gene construct.