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Premature chain termination mutation causing Duchenne muscular dystrophy

Institute for Molecular Genetics, Baylor College of Medicine, Houston, TX (Dr. Clemens, P.A. Ward, and Drs. Caskey and Fenwick)
Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX (Dr. Caskey)
Genetics Department and Research Institute, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada (D.E. Bulman).

We identified a premature chain termination mutation in two brothers with Duchenne muscular dystrophy and correlated the mutation in one of the brothers with immunologic detection of dystrophin in skeletal muscle. Southern and polymerase chain reaction (PCR) studies of genomic DNA from the affected boys showed no major gene rearrangements. However, the noted absence of a Hind III Southern fragment containing the proximal portion of exon 48 led to the identification of a point mutation that creates a new Hind III restriction site in that exon. Exon 48 was amplified by PCR from DNA of the patients and other family members and digested with Hind III to show the mutation in the two boys and also in their mother and maternal grandmother. Direct DNA sequencing demonstrated a cytosine-to-thymine transition at nucleotide 7163 of dystrophin that converts a glutamine codon (CAA) to an ochre chain termination codon (UAA). This mutation predicts a truncated dystrophin missing the distal spectrin-like repeat region, the cysteine-rich domain, and the carboxy terminal. Immunohistochemistry of skeletal muscle from one of the affected boys revealed membrane-localized dystrophin in the majority of fibers detected by anti-dystrophin antibodies against (1) the amino terminal and (2) part of the spectrin-like repeat region; both regions would be present in the truncated dystrophin predicted by the chain termination mutation. This suggests that the carboxy terminal may not be an absolute requirement for dystrophin membrane localization. Very few muscle fibers also showed peripheral immunostaining using anti-dystrophin antibodies against the carboxy terminal, suggesting gene reversion, suppression, or read-through in these rare fibers.

Supported by a Neuromuscular Disease Genetics Research grant and a Task Force on Genetics grant, both from the Muscular Dystrophy Association, and by the National Institutes of Health grant No. M01 RR-00188, General Clinical Research Center for Children. P.R.C. was a recipient of a Muscular Dystrophy Association postdoctoral research fellowship, and C.T.C. is an investigator of the Howard Hughes Medical Institute.

Address correspondence and reprint requests to Dr. Paula R. Clemens, Institute for Molecular Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.

Received November 11, 1991. Accepted for publication in final form February 19, 1992.

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				J. R. Mendell, Z. Sahenk, and T. W. Prior The Childhood Muscular Dystrophies: Diseases Sharing a Common Pathogenesis of Membrane Instability J Child Neurol, March 1, 1995; 10(2): 150 - 159. [Abstract] [PDF]