of Structural Proteins

Figure 12-16 Pseudohypertrophy of the calves due to the replacement of normal muscle tissue with connective tissue and fat in an 8-year-old boy with Duchenne muscular dystrophy. See Sources & Acknowledgments.

The Clinical Phenotype of Becker Muscular Dystrophy.


Figure 12-17 Microscopic visualization of the effect of mutations in the dystrophin gene in a patient with Becker muscular dystrophy (BMD) and a patient with Duchenne muscular dystrophy (DMD). Left column, Hematoxylin and eosin staining of muscle. Right column, Immunofluorescence microscopy staining with an antibody specific to dystrophin. Note the localization of dystrophin to the myocyte membrane in normal muscle, the reduced quantity of dystrophin in BMD muscle, and the complete absence of dystrophin from the myocytes of the DMD muscle. The amount of connective tissue between the myocytes in the DMD muscle is increased. See Sources & Acknowledgments.

The Genetics of Duchenne Muscular Dystrophy and Becker Muscular Dystrophy


BMD accounts for approximately 15% of the mutations at the locus. An important genetic distinction between these allelic phenotypes is that whereas DMD is a genetic lethal, the reproductive fitness of males with BMD is high (up to approximately 70% of normal), so that they can transmit the mutant gene to their daughters. Consequently, and in contrast to DMD, a high proportion of BMD cases are inherited, and relatively few (only approximately 10%) represent new mutations.

The DMD Gene and Its Product.


Figure 12-18 A representation of the full-length dystrophin protein, the corresponding cDNA, and the distribution of representative deletions in patients with Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy (DMD). Partial duplications of the gene (not shown) account for approximately 6% of DMD or BMD alleles. The actin-binding domain links the protein to the filamentous actin cytoskeleton. The rod domain presumably acts as a spacer between the N-terminal and C-terminal domains. The cysteine-rich domain mediates protein-protein interactions. The C-terminal domain, which associates with a large transmembrane glycoprotein complex (see Fig. 12-19), is also found in three dystrophin-related proteins (DRPs): utrophin (DRP-1), DRP-2, and dystrobrevin. The protein domains are not drawn to scale.

The Molecular and Physiological Defects in Becker Muscular Dystrophy and Duchenne Muscular Dystrophy.


Figure 12-19 Diagnosis of Duchenne muscular dystrophy (DMD) involves screening for deletions and duplications by a procedure called multiplex ligation-dependent probe amplification (MLPA). MLPA allows the simultaneous analysis of all 79 exons of the DMD gene in a single DNA sample and can detect exon deletions and duplications in males or females. Each amplification peak represents a single DMD gene exon, after separation of the amplification products by capillary electrophoresis. Top panel, The amplification profiles of 16 exons of a normal male sample. Control (C) DNAs are included at each end of the scan. The MLPA DNA fragments elute according to size, which is why the exons are not numbered sequentially. Bottom panel, The corresponding amplification profile from a DMD patient with a deletion of exons 46 and 47. See Sources & Acknowledgments.

The absence of dystrophin in DMD destabilizes the myofiber membrane, increasing its fragility and allowing increased Ca++ entry into the cell, with subsequent activation of inflammatory and degenerative pathways. In addition, the chronic degeneration of myofibers eventually exhausts the pool of myogenic stem cells that are normally activated to regenerate muscle. This reduced regenerative capacity eventually leads to the replacement of muscle with fat and fibrotic tissue.

The Dystrophin Glycoprotein Complex (DGC).


Figure 12-20 In muscle, dystrophin links the extracellular matrix (laminin) to the actin cytoskeleton. Dystrophin interacts with a multimeric complex composed of the dystroglycans (DG), the sarcoglycans, the syntrophins, and dystrobrevin. The α,β-dystroglycan complex is a receptor for laminin and agrin in the extracellular matrix. The function of the sarcoglycan complex is uncertain, but it is integral to muscle function; mutations in the sarcoglycans have been identified in limb girdle muscular dystrophies (LGMDs) types 2C, 2D, 2E, and 2F. Mutations in laminin type 2 (merosin) cause a congenital muscular dystrophy (CMD). The branched structures represent glycans. The WW domain of dystrophin is a tryptophan-rich, protein-binding motif.

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Nov 27, 2016 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on of Structural Proteins

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