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The discovery of dystrophin, the protein product of the Duchenne muscular dystrophy gene.

ABSTRACT: Duchenne muscular dystrophy was a well-established medical and genetic enigma by the 1970s. Why was the new mutation rate so high in all world populations? Why were affected boys doing well in early childhood, but then showed relentless progression of muscle wasting? What was wrong with the muscle? The identification of the first fragments of DMD gene cDNA in 1986, prediction of the entire 3685 amino acid protein sequence, and production of antibodies to dystrophin, both in 1987, provided key tools to understand DMD genetics and molecular pathology. The identification of dystrophin nucleated extensive research on myofiber membrane cytoskeleton, membrane repair, muscle regeneration, and failure of regeneration. This in turn led to molecular therapeutics based on understanding of dystrophin structure and function. This historical perspective describes the events surrounding the initial identification of the dystrophin protein.

SUBMITTER: Hoffman EP

PROVIDER: S-EPMC7540009 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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The discovery of dystrophin, the protein product of the Duchenne muscular dystrophy gene.

Hoffman Eric P EP

The FEBS journal 20200721 18

Duchenne muscular dystrophy was a well-established medical and genetic enigma by the 1970s. Why was the new mutation rate so high in all world populations? Why were affected boys doing well in early childhood, but then showed relentless progression of muscle wasting? What was wrong with the muscle? The identification of the first fragments of DMD gene cDNA in 1986, prediction of the entire 3685 amino acid protein sequence, and production of antibodies to dystrophin, both in 1987, provided key to ...[more]

PMID: 32608079

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Project description:Supramolecular membrane complexes of low abundance are difficult to study by routine bioanalytical techniques. The plasmalemmal complex consisting of sarcoglycans, dystroglycans, dystrobrevins and syntrophins, which is closely associated with the membrane cytoskeletal protein dystrophin, represents such a high?molecular?mass protein assembly in skeletal muscles. The almost complete loss of the dystrophin isoform Dp427?M and concomitant reduction in the dystrophin?associated glycoprotein complex is the underlying cause of the highly progressive neuromuscular disorder named Duchenne muscular dystrophy. This gives the detailed characterization of the dystrophin complex considerable pathophysiological importance. In order to carry out a comprehensive mass spectrometric identification of the dystrophin?glycoprotein complex, in this study, we used extensive subcellular fractionation and enrichment procedures prior to subproteomic analysis. Mass spectrometry identified high levels of full?length dystrophin isoform Dp427?M, ?/??dystroglycans, ?/?/?/??sarcoglycans, ?1/?1/?2?syntrophins and ?/??dystrobrevins in highly purified sarcolemma vesicles. By contrast, lower levels were detected in transverse tubules and no components of the dystrophin complex were identified in triads. For comparative purposes, the presence of organellar marker proteins was studied in crude surface membrane preparations vs. enriched fractions from the sarcolemma, transverse tubules and triad junctions using gradient gel electrophoresis and on?membrane digestion. This involved the subproteomic assessment of various ion?regulatory proteins and excitation?contraction coupling components. The comparative profiling of skeletal muscle fractions established a relatively restricted subcellular localization of the dystrophin?glycoprotein complex in the muscle fibre periphery by proteomic means and clearly demonstrated the absence of dystrophin from triad junctions by sensitive mass spectrometric analysis.

Dataset Information

The discovery of dystrophin, the protein product of the Duchenne muscular dystrophy gene.

Publications

The discovery of dystrophin, the protein product of the Duchenne muscular dystrophy gene.

Similar Datasets

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