Cloning of the breakpoint of an X;21 translocation associated with Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder which affects approximately 1 in 3,300 males, making it the most common of the neuromuscular dystrophies. The biochemical basis of the disease is unknown and as yet no effective treatment is available. A small number of females are also affected with the disease, and these have been found to carry X; autosome translocations involving variable autosomal sites but always with a breakpoint within band Xp21 of the X chromosome (implicated by other kinds of genetic evidence as the site of the DMD lesion). In these female patients the normal X chromosome is preferentially inactivated, which it is assumed silences their one normal DMD gene, leading to expression of the disease. In one such affected female the autosomal breakpoint lies in the middle of the short arm of chromosome 21, within a cluster of ribosomal RNA genes. Here we have used rRNA sequences as probes to clone the region spanning the translocation breakpoint. A sequence derived from the X-chromosomal portion of the clone detects a restriction fragment length polymorphism (RFLP) which is closely linked to the DMD gene and uncovers chromosomal deletions in some male DMD patients.

Chromosomal Aberrations and Schizophrenia

“…The fortuitous observation of these rare events has substantially aided in, for example, the physical mapping and subsequent cloning of the gene causing Duchenne muscular dystrophy (DMD) (Ray et al, 1985). In addition, associations of specific diseases with chromosomal aberrations have suggested candidate regions for linkage studies.…”

Recombinant DNA techniques in the diagnosis of inherited disorders.

“…The first X-linked disease for which a linked RFLP was identified was Duchenne muscular dystrophy in 1982 (20). A concentrated effort on the Duchenne muscular dystrophy region has now produced a large number of linked genetic markers and has brought investigators to the very brink of identifying the gene defect itself (21)(22)(23). The ease of analysis of sex-linked disorders, due to the presence of a single allele at each locus in males, has allowed the detection of linked markers for Alport syndrome, Becker muscular dystrophy, X-linked Charcot-MarieTooth disease, choroideremia, Fragile X mental retardation syndrome, Menkes disease, ocular albinism, X-linked retinitis pigmentosa, and retinoschisis (24).…”

Improved diagnosis of Duchenne/Becker muscular dystrophy.

“…When these early genomic DNA probes were used to examine DNA from patients with DMD and BMD, it was found that up to 5% had gene deletions (10)(11)(12). However, linkage analysis in families without detectable deletions suggested that mutations causing DMD could occur at great distances on either side of the cloned probes (13,14).…”