We describe here a BMD patient who belongs to a small class of subjects with large in frame deletions of the dystrophin gene that remove apparently dispensable coding sequence, thereby producing functional truncated dystrophin.
In order to investigate if the same apparent decrease in dystrophin negative fibers with aging observed in mouse mdx female heterozygotes also occurs in carriers of the DMD and BMD gene, we have studied the muscle of 29 DMD carriers (19 adults and 10 young daughters of obligate carriers, including 3 manifesting carriers) and 5 adult asymptomatic heterozygotes for Becker dystrophy (BMD).
The results of IF were largely compatible with those from WB but differences were also observed, e.g. one barely symptomatic BMD patient with dystrophin of increased molecular weight showed normal IF.
Quantitative studies indicated that the relative abundance of dystrophin in patients with a severe (DMD), intermediate, or mild (BMD) phenotype may overlap, therefore suggesting that differential diagnosis of disease severity based entirely on dystrophin quantitation may be unsatisfactory.
Here we use a new monoclonal antibody directed against an peptide in the C-terminal end of the dystrophin molecule to show that the C-terminus is preserved in 30 BMD and 24 control skeletal muscles but not in 21 DMD specimens.
This observation has led to the suggestion that BMDdystrophin molecules, which are usually smaller than normal due to the presence of "in frame" gene deletions, cannot be assembled into a complete lattice network under the plasma membrane and instead form isolated patches.
Eighty-six percent of BMD patients with dystrophin of altered size have deletions or duplications, and the observed sizes of dystrophin fit well with predictions based on DNA data.
All 4 patients had clear abnormalities of dystrophin, and were diagnosed as having Becker muscular dystrophy by both immunofluorescence and immunoblot examinations; that is, dystrophin of an abnormal molecular mass was visualized in muscle cryosections as "patchy" or discontinuous immunostaining at the surface membrane of the muscle fibers.
Molecular deletion screening with cDNA probes from the dystrophin gene was undertaken in patients with Becker muscular dystrophy from 58 separate families.
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.
We describe two brothers with identical inherited deletions of one single exon within the middle of the DMD gene; one brother has Becker muscular dystrophy diagnosed at 11 years of age, whereas the older brother is normal at 18.
The distribution and frequency of deletions spanning the entire locus suggests that many "in-frame" deletions of the dystrophin gene are not detected because the individuals bearing them are either asymptomatic or exhibit non-DMD/non-BMD clinical features.
Thirty-three patients with BMD or LGD (thirty isolated and three with an affected brother) were screened with a panel of cDNA probes for the whole dystrophin gene.
Since deletions were not detectable, an X-chromosomal segment, carrying DNA markers for the dystrophin gene and its flanking regions was reconstructed; this demonstrated Becker muscular dystrophy is the most probable primary cause of illness in these families.
This study consisted of 1) molecular deletion analyses in patients with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) using the entire cDNA for the DMD gene as hybridization probes, 2) RFLP analyses in a large number of Japanese normal women using 11 DMD-linked cloned DNAs as probes, and 3) segregation analyses with these RFLP data in 17 DMD families in which prenatal or carrier diagnosis was required.
In the course of a systematic survey of DMD and BMD patients with intronic probes and with cDNA probes covering three-fourths of the coding sequence, 45 molecular deletions within the DMD gene were investigated.
The distribution of deletions across the gene region shows at least one region (detected by P20) prone to deletion mutations in both DMD and BMD patients.
Given the observed clinical variability of Becker dystrophy, it appears that dystrophin analysis is required for accurately distinguishing between Becker dystrophy and clinically similar autosomal recessive myopathies.
Using a complementary DNA subclone of the DMD gene we have screened 66 DMD and BMD patients who had not previously shown deletions with the probes then available.