Dystrophin

Alpha helices are sufficiently versatile to produce many very different classes of structures. In membrane-bound proteins, the regions inside the membranes are frequently a helices whose surfaces are covered by hydrophobic side chains suitable for the hydrophobic environment inside the membranes. Membrane-bound proteins are described in Chapter 12. Alpha helices are also frequently used to produce structural and motile proteins with various different properties and functions. These can be typical fibrous proteins such as keratin, which is present in skin, hair, and feathers, or parts of the cellular machinery such as fibrinogen or the muscle proteins myosin and dystrophin. These a-helical proteins will be discussed in Chapter 14. 

The leucine zipper DNA-binding proteins, described in Chapter 10, are examples of globular proteins that use coiled coils to form both homo- and heterodimers. A variety of fibrous proteins also have heptad repeats in their sequences and use coiled coils to form oligomers, mainly dimers and trimers. Among these are myosin, fibrinogen, actin cross-linking proteins such as spectrin and dystrophin as well as the intermediate filament proteins keratin, vimentin, desmin, and neurofilament proteins. 

A comparison of the amino acid sequences of dystrophin, a-actinin, and spectrin. The potential hinge segments in die dystrophin structure are indicated. 

Koenig, M., and Knnkel, L., 1990. Detailed analysis of die repeat domain of dystrophin reveals four potendal hinge segments that may confer flexibility. of Biological Chemistry 265 4560-4566. 

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

DMD and BMD DMD and BMD are caused by the absence or deficiency of dystrophin a membrane-associated protein, resulting in increased Ca2+ concentration in muscle, loss of Ca2+ homeostasis, and inappropriate calpain activity36... 

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... 

A number of additional proteins play various roles in the structure and function of muscle. They include titin (the largest protein known), nebufin, a-actinin, desmin, dystrophin, and calcineurin. Some properties of these proteins are summarized in Table 49-2. 

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

Abnormalities of myocardial contractile and structural proteins P-Myosin heavy chains, troponin, tropomyosin, dystrophin... 

Another type of cardiomyopathy is termed dilated cardiomyopathy. Mutations in the genes encoding dystrophin, muscle LIM protein (so called because it was found to contain a cysteine-tich domain originally detected in three proteins Lin-II, Isl-1, and Mec-3), and the cyclic response-element binding ptotein (CREB) have been implicated in the causation of this condition. The first two proteins help organize the conttactile ap-params of cardiac muscle cells, and CREB is involved... 

Figure 49-13. Simplified scheme of the causation of familial hypertrophic cardiomyopathy (MIM 192600) due to mutations in the gene encoding fi-myosin heavy chain. Mutations in genes encoding other proteins, such as the troponins, tropomyosin, and cardiac myosin-binding protein C can also cause this condition. Mutations in genes encoding yet other proteins (eg, dystrophin) are involved in the causation of dilated cardiomyopathy.

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

McArdle, A., Edwards, R.H.T. and Jackson, M.J. (1992). Accumulation of calcium by normal and dystrophin-deficient muscle during contractile activity in vitro . Clin. Sci. 82, 455-459. 

Mundegar et al.71 applied a modified AR protocol to unfixed frozen sections with the goal of reducing background. Their study was designed to detect a 427 kD subsarcolemmal protein dystrophin in mdx mouse skeletal muscle... 

Yin H, Lu Q, Wood M (2008) Effective exon skipping and restoration of dystrophin expression by peptide nucleic acid antisense oligonucleotides in mdx mice. Mol Ther 16 38 15... 

Gussoni, E., Soneoka, Y., Strickland, C. D. et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401 390-394,1999. 

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