Dystrophin dystrophy

Worton, R., 1995. Mnscnlar dystrophies Diseases of die dystrophin-glycoprotein complex. Science 270 755-756. 

Figure 1. Immunofluorescent labeling of dystrophin in the Xp21 muscular dystrophies. In normal muscle, clear uniform labeling is present at the membrane of each muscle fiber. In Becker muscular dystrophy (BMD), there is inter- and intrafiber variation in labeling intensity. In Duchenne muscular dystrophy (DMD), most fibers are devoid of labeling (note, however, that in most biopsies occasional fibers exhibit weak labeling). In the biopsy from a manifesting carrier, some fibers show normal labeling and others are negative. In the former, the normal X-chromosome is active while in the latter the abnormal X-chromosome is active.

Bushby, K., Gardner-Medwin, D. (1993). The clinical, genetic and dystrophin characteristics of Becker muscular dystrophy. I. Natural History. J. Neurol. 240. 98-104. 

Dickson, G., Dunckley, M. (1993). Human dystrophin gene transfer Genetic correction of dystrophin deficiency. In Molecular and Cell Biology of Muscular Dystrophy (Partridge, T., ed.), pp. 283-302, Chapman Hall, London. 

Hoffrnan, E.P., Kunkel, L.M. (1989). Dystrophin abnormalities in Duchenne/Becker muscular dystrophy. Neuron 2, 1019-1029. 

MUTATIONS IN THE GENE ENCODING DYSTROPHIN CAUSE DUCHENNE MUSCULAR DYSTROPHY... 

Dystrophin Attached to plasma-lemma Deficient in Duchenne muscular dystrophy. Mutations of its gene can also cause dilated cardiomyopathy. 

Duchenne-type muscular dystrophy is due to mutations in the gene, located on the X chromosome, encoding the protein dystrophin. 

Molecular diagnostics approaches to carrier status for Duchenne muscular dystrophy are based on the discovery of the presence of a deletion in the gene for dystrophin. Sometimes, the testing approach provides a probability or likelihood estimate of an individual being a carrier (e.g., the use of indirect or linkage analysis for DMD when a deletion is not detectable), rather than clear documen-... 

Zn-binding domain, present in CBP/p300 and Dystrophin. In Dystrophin, domain is implicated in Calmodulin binding. Mis-sense mutation of conserved cysteine correlates with Duchenne muscular dystrophy. 

Answer B. In-frame deletions or insertions typically produce an altered protein product (dystrophin), but the alteration is mild enough so that Becker muscular dystrophy results. Frame-shifts usually produce a truncated protein because a stop codon is eventually encountered. The truncated protein is degraded, resulting in an absence of dystrophin and a more severe disease phenotype. 

In 1987 the gene responsible for muscular dystrophy was identified, leading to the isolation of a protein, known as dystrophin, which is either totally absent in Duchenne, or partially absent in the Becker type. The protein is located on the inside of the plasma membrane of all muscles (and some neurones). Although its precise function is not known, the mutant form results in structural abnormalities of the plasma member which results in degradation of myofibrils, but the hnk between the abnormalities of the membrane and degradation is not known. One theory is that it leads to an increase in the activity of a Ca " ion channel in the membrane and, therefore, a marked increase in the Ca ion concentration in the cytosol. This chronic elevation results in the activation of calpain, which leads to protein breakdown and the degeneration within the fibre (Chapter 13). 

Hoffman EP, Brown RH, Jr., Kunkel LM. Dystrophin the protein product of the Duchenne muscular dystrophy locus. Cell. Dec 24 1987 51(6) 919-928. 

A four-year-old child who becomes easily tired and has trouble walking is diagnosed with Duchenne muscular dystrophy, an X-linked recessive disorder. Genetic anal ysis shows that the patient s gene for the muscle protein dystrophin contains a mutation in its promoter region. What would be the most likely effect of this mutation ... 

Schematic model of the dystrophin-glycoprotein complex. Courtesy of Kevin P. Campbell. See Lim and Campbell1 Abbreviations LGMD, Limb Girdle muscular dystrophy CMD, congenital muscular dystrophy DMD / BMD, Duchenne / Becker muscular dystrophies.

Nguyen thi Man and Morris, G. E (1993) Use of epitope libraries to identify exon-specific monoclonal antibodies for characterization of altered dystrophins in muscular dystrophy Am J Hum Genet 52, 1057—1066. 

Thanh, L T, Nguyen thi Man, Hori, S, Sewry, C A, Dubowitz V., and Morris, G E. (1995) Characterization of genetic deletions in Becker Muscular Dystrophy using monoclonal antibodies against a deletion-prone region of dystrophin. Am J Med Genet 58, 177-186. 

Sedgwick, S. G, Nguyen thi Man, Ellis, J M., Crowne, H, and Morris, G. E (1991) Rapid mapping by transposon mutagenesis of epitopes on the muscular dystrophy protein, dystrophin. Nucleic Acids Res 19, 5889-5894. 

Dystrobrevins are a small family of dystrophin-related proteins encoded by two genes, one of which—Q-dystrobrevin—encodes at least three proteins all expressed in cardiac and skeletal muscle. o-Dystrobrevin is a key component of the DPC, and its loss results in neuromuscular junction defects and muscular dystrophy. It is a cytoplasmic protein indirectly linked with the transmembrane sarcoglycan components via dystrophin and other components of the DPC (Fig. 4) (Blake and Martin-Rendon, 2002). Recently, two novel type IV IF proteins—syncoilin (Newey et al.,... 

DMD is a severe X-linked recessive, progressive muscle wasting disease that affects approximately 1 in 3500 newborn males (Emery, 1991). An allelic variant of DMD is also known, referred to as Becker muscular dystrophy (BMD). It has a later onset and lesser phenotype than DMD, resulting in longer life expectancy (reviewed in O Brien and Kunkel, 2001). DMD is caused by mutations in the DMD gene that encodes the cytoskeletal linker protein dystrophin. The vast majority of DMD mutations result in the... 

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