Molecular and clinical correlations of deletions leading to Duchenne and Becker muscular dystrophies

Abstract

Human DMD cDNA probes have been used to delineate possible deletions in 160 affected males. Approximately 56% of these individuals had detectable deletions, 29% of which mapped to a region centered around 500 kb from the 5' end of the gene whereas 69% mapped to a region located centrally 1,200 kb from the 5' end. We have observed no correlation between the extent of a deletion, its location, and clinical severity of the associated disease. For some cases with deletions in the two high-frequency deletion regions, the predicted effect upon translational reading frame of the resultant dystrophin mRNA did not correlate with the associated disease phenotype.

Comparative study on deletions of the dystrophin gene in three Asian populations

“…The 3.0-Mb dystrophin gene is the largest known human gene with a total coding sequence of 11,220 bp transcribed from 79 exons. Generally, about 60% of all DMD and BMD cases are due to gross gene deletions, 5% to duplications, and the remaining 35% to point mutations (Baumbach et al 1989;Gillard et al 1989). Frame-shift mutations that disrupt the translational reading frame lead to a truncated nonfunctional dystrophin protein that results in severe DMD, whereas mutations that maintain the reading frame result in a semifunctional protein that causes the milder BMD phenotype (Monaco et al 1988).…”

Gene deletions in Japanese patients with Duchenne and Becker muscular dystrophy

“…Since the positions of exon-intron borders and the distribution of the exons within the HindlII fragments detected by probe 1-2a to the proximal region of 10 have recently been published (Malhorta et aI., 1988;Baumbach et al, 1989;Koenig et al, 1989), we were able to investigate the hypothesis that the phenotypic differences between BMD and DMD depend upon whether or not the translational reading frame is maintained. The deletions of 4.2 to 4.6 HindlII fragments in the probe 1-2a lead to apparent frame shift (Tables 1-4).…”

“…With the cDNA probes, Koenig et al (1987) detected deletions of HindlII-digested DNAs in more than 50 ~ of DMD patients. And there have been many reports as for DNA deletions of Caucasian DMD and BMD patients, and no simple correlation between the deletion size or location and the clinical severity of the disease has been observed (Malhotra et al, 1988;Hart et al, 1989;Lindl6f et al, 1989;Baumbach et al, 1989). One possible explanation for phenotypic difference in BMD and DMD has been reported to depend on whether or not the translational reading frame is maintained and some functional protein is produced (Monaco et al, 1988;Forrest et al, 1988), and this theory was proved to be true of 92~ of Caucasian DMD and BMD patients (Koenig et al, 1989).…”

“…One possible explanation for phenotypic difference in BMD and DMD has been reported to depend on whether or not the translational reading frame is maintained and some functional protein is produced (Monaco et al, 1988;Forrest et al, 1988), and this theory was proved to be true of 92~ of Caucasian DMD and BMD patients (Koenig et al, 1989). But in some BMD patients, the deletions disrupted the translational reading frame, indicating that other factors, which compensate for the frame-shift mutation should exist (Malhotra et al, 1988;Baumbach et aL, 1989). Sugino et al (1989) reported that DNA deletions were detected in 43~o of Japanese DMD patients, and deletion hot spots were also located in the proximal region and the central region of the gene.…”

Gene therapy for Duchenne muscular dystrophy

“…It is important to note that there is no clear correlation between the location/size of the deletion and the severity and progression of these two allelic disorders [8]. Mutations that disrupt the normal openreading frame of the dystrophin mRNA typically prevent expression of a functional protein, while in-frame deletions can yield stable truncated dystrophins with partial functionality, resulting in the milder BMD [5,9]. One BMD patient with an in-frame deletion of exons 17-48 has captured much attention for remaining ambulatory into his 70s [10].…”