Nonsense mutations in a Becker muscular dystrophy and an intermediate patient

• Published in: Human mutation Vol. 7; no. 1; pp. 72 - 75
• Main Authors: Prior, Thomas W., Bartolo, Claire, Papp, Audrey C., Snyder, Pamela J., Sedra, Mary S., Burghes, Arthur H.M., Mendell, Jerry R.
• Format: Journal Article
• Language: English
• Published: New York Wiley Subscription Services, Inc., A Wiley Company 1996
• Subjects: Codon, Nonsense; Dystrophin - genetics; Dystrophin - immunology; Exons; Humans; Immunohistochemistry; Muscular Dystrophies - genetics; Muscular Dystrophies - metabolism; Nucleic Acid Heteroduplexes - analysis; Point Mutation; Polymerase Chain Reaction
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/(SICI)1098-1004(1996)7:1<72::AID-HUMU13>3.0.CO;2-P

There are now several reports of small mutations detected in the dystrophin gene in Duchenne muscular dystrophy (DMD) patients. The majority of these mutations have resulted in truncated dystrophins lacking part or all of the C-terminus. The truncated proteins are presumably unstable, and little or no dystrophin is detected on Western blot analysis from muscle biopsy samples. Therefore, these types of mutations provide little information on structural-functional relationships in the dystrophin protein. Currently two Becker muscular dystrophy (BMD) point mutations have been reported. Both of these mutations affected normal splicing and resulted in the production of dystrophins with in-frame deletions. The BMD mutations were consistent with the reading frame theory, which hypothesizes that deletions or duplications causing BMD allow production of dystrophin because the translational reading frame is maintained. Since BMD patients and patients with intermediate (IMD) phenotype (ambulatory after the age of 12 but not after the age 16) often produce dystrophin, the identification of mutations in these patients is extremely important. The types and locations of point mutations in this group of patients may provide us with important insight into the function of dystrophin as well as defining the essential regions and conformations necessary for dystrophin stability. We have analyzed genomic DNA from 40 BMD and 8 IMD patients for point mutations. No deletions or duplications were previously identified in these patients by our diagnostic multiplex PCR and Southern blotting. Approximately 85% of the dystrophin gene exons (exons 1-4, 6-14, 16, 17, 19-30, 32-35, 37-57, 59, 60, 62-71, and 73-76) have been completely screened using a heteroduplex method. From these 48 patients we have identified mutations in one BMD and one intermediate patient. We now describe the mutations, as well as the protein and RNA analysis, and discuss the possible mutations mechanisms.