A CASE OF BECKER MUSCULAR-DYSTROPHY RESULTING FROM THE SKIPPING OF 4 CONTIGUOUS EXONS (71-74) OF THE DYSTROPHIN GENE DURING MESSENGER-RNA MATURATION

The mutations in one-third of both Duchenne and Becker muscular dystro phy patients remain unknown be cause they do not involve gross rearran gements of the dystrophin gene, Here we report the first example of mu ltiple exon skipping during the splicing of dystrophin mRNA precursor encoded by an apparently normal dystrophin gene, A 9-year-old Japanese boy exhibiting excessive fatigue and high serum creatine kinase activ ity was examined for dystrophinopathy. An immunohistochemical study of muscle tissue biopsy disclosed faint and discontinuous staining of ti le N-terminal and rod domains of dystrophin but no staining at all of the C-terminal domain of dystrophin. The dystrophin transcript ii rtm muscle tissue was analyzed by the reverse transcriptase polymerase cha in reaction, An amplified product encompassing exons 67-79 of dystroph in cDNA was found to be smaller than that of the wild-type product, Se quence analysis of this fragment showed that the 3' end of tron 70 was directly connected to the 5' end of exon 75 and, thus, that exons 71- 74 were completely absent, As a result, a truncated dystrophin protein lacking 110 amino acids from the C-terminal domain should result from translation of this truncated mRNA, and the patient was diagnosed as having Becker muscular dystrophy :It the molecular level, Genomic DNA was analyzed to identify the cause of the disappearance of these exons , Every exon-encompassing region could be amplified from genomic DNA, indicating that the dystrophin gene is intact, Furthermore, sequencing of these amplified products dill not disclose any particular nucleoti de change that could be responsible for the multiple exon skipping obs erved. Considering that exons 71-74 are spliced out alternatively in s ome tissue-specific isoforms, to suppose that the alternative splicing machinery is present in the muscle tissue of the index case and that it is activated by an undetermined mechanism is reasonable, These resu lts illustrate a novel genetic anomaly that results in dystrophinopath y.