Observations on the pathogenesis of Duchenne muscular dystrophy in the light of recent progress in molecular genetics

Abstract

The gene on the X chromosome which, when abnormal, causes Duchenne muscular dystrophy (DMD) is estimated to be at least 1800 kb in length, making it possibly the largest in the entire human genome. Cloned mRNA derived from the gene indicates that it codes for a protein with a molecular weight of approximately 400,000 daltons. This protein, which is expressed in very low concentration (one molecule to each of 15 muscle nuclei), has been named dystrophin. It is anticipated that the molecular biology of dystrophin will now be elucidated quickly so that its function in the cell is revealed and steps to correct the biochemical defect initiated. It is also possible that the gene codes for a family of proteins and that these reside within the intermediate filament system of the cytoskeleton. Candidate proteins are spectrin, nebulin and titin, as well as dystrophin. In the light of these advances in the molecular genetics of DMD, it is timely for the myopathologist to suggest possible mechanisms of aetiopathogenesis for the disorder. In this regard the first unequivocal lesion in muscle biopsies in DMD is focal muscle fibre necrosis. Electron microscopy (EM) reveals excessive hypercontraction of sarcomeres, especially in the early stages. These hypercontracted zones correspond to the 'hyalinized' muscle fibres typical of the disorder. It seems possible that such hypercontractions cause tears in the plasma membrane of the muscle fibre which may be weakened by an abnormality of the intermediate filaments which underlie the lipid bilayer.(ABSTRACT TRUNCATED AT 250 WORDS)