Disease relevance of DMD

• Partial deletions of the dystrophin gene are the predominant genetic lesions in Duchenne (DMD) and Becker (BMD) muscular dystrophies [1].
• Sarcolemmal expression occurs on regenerating fibers, irrespective of the disease, and is also seen on mature fibres in Duchenne and Becker muscular dystrophies (DMD, BMD), and inflammatory myopathies [2].
• Although the molecular defect causing Duchenne/Becker muscular dystrophy (DMD/BMD) was identified nearly 20 years ago, the development of effective therapeutic strategies has nonetheless remained a daunting challenge [3].
• In Duchenne/Becker dystrophy (DMD/BMD) and in polymyositis (PM) or dermatomyositis (DM) DRP was present throughout the extrajunctional surface membrane of extra- and intrafusal muscle fibers, particularly regenerating ones [4].
• 5'-mutations in the dystrophin gene can result in cardiomyopathy without clinically-apparent skeletal myopathy [5].

Psychiatry related information on DMD

• The role of dystrophin in the brain is not clear, though one-third of Duchenne muscular dystrophy patients exhibit some degree of mental retardation [6].
• Sixty-eight patients with DMD underwent psychometric assessment before or after thalamic surgery [7].
• Older boys with DMD were at greater risk of depressive disorder than younger boys [8].
• Other psychological test data revealed no specific personality patterns in the DMD patients, particularly no pattern of conversion hysteria or hysteria [7].
• Dysthymic disorder and major depressive disorder occurred significantly more often among DMD boys than controls [8].

High impact information on DMD

• Dystrophin is also the prototype of a family of dystrophin-related proteins, many of which are found in muscle [9].
• The X-linked muscle-wasting disease Duchenne muscular dystrophy is caused by mutations in the gene encoding dystrophin [9].
• Mutations in many components of the dystrophin protein complex cause other forms of autosomally inherited muscular dystrophy, indicating the importance of this complex in normal muscle function [9].
• Dystrophin is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina [9].
• Function and genetics of dystrophin and dystrophin-related proteins in muscle [9].

Chemical compound and disease context of DMD

• We report three cases who presented with only mild or no muscle weakness but had elevated serum creatine kinase activity and dystrophin immunolabelling indistinguishable from normal, making a pathological diagnosis difficult [10].
• Mental retardation in our patient and absence of the b-wave in his electroretinogram indicate that central nervous functions of dystrophin isoforms also depend on the presence of cysteine 3340 [11].
• Type 2 vacuoles were lined by dystrophin and beta-spectrin and were most common in adult acid maltase deficiency, chloroquine myopathy, and periodic paralysis [12].
• Dystrophin, the protein product of the Duchenne/Becker muscular dystrophy gene has been localized in muscle to the inner surface of the plasma membrane and is likely to be associated with an integral membrane glycoprotein [13].
• We have cloned the cDNA encoding the 87K protein from Torpedo electric organ, and the predicted protein sequence is homologous to the C-terminal domains of dystrophin, the protein product of the Duchenne muscular dystrophy gene [14].

Biological context of DMD

• According to the reading frame hypothesis [1], any deletion disrupting the translational reading frame of the mRNA cannot result in expression of the dystrophin molecule and should lead to severe phenotypes of DMD [1].
• Chromosome 6-encoded dystrophin-related-protein (DRP) shows significant structural similarities to dystrophin at the carboxyl terminus, though the two proteins are encoded on different chromosomes [15].
• On the basis of its alternative splicing, dystrophin may thus be present in two functionally distinct populations [16].
• The distribution of exons within the genomic DNA has similarities to that of the dystrophin gene [17].
• The molecular stimulus for the marked upregulation of DRP in DMD/BMD and in the inflammatory myopathies is not known [4].

Anatomical context of DMD

• Dystrophin-related protein was present in about the same amounts and distribution in normal and DMD cultured myoblasts and myotubes [4].
• These findings seem to dampen the enthusiasm raised by the prospect of DMD treatment by utrophin rescue in skeletal muscle fibers, as the myocardium would still remain severely affected [18].
• In DMD patients, NADPH-d reactivity was increased and mainly localized in regenerating muscle fibers [19].
• During the past year significant progress has been made in understanding how dystrophin deficiency leads to muscle cell necrosis in Duchenne muscular dystrophy and Becker muscular dystrophy [20].
• Dystrophin interacts with a glycoprotein complex spanning the muscle sarcolemma, effectively linking the actin cytoskeleton to the extracellular matrix [20].

Associations of DMD with chemical compounds

• In contrast to normal cultures, the utrophin content of long-term dexamethasone-treated DMD myotube cultures was significantly greater than that of the corresponding untreated cultures [21].
• The carboxyl terminus of dystrophin is required for glycoprotein binding [20].
• Electric tissue syntrophin, originally described as an M(r) 58,000 postsynaptic protein having homologs in mammalian muscle, was previously shown to associate with dystrophin in Triton extracts of Torpedo postsynaptic membranes [22].
• The largest open reading frame isolated shows 94% homology (86% identity) to the Torpedo 87 kDa protein and 50% homology to the cysteine-rich and carboxy-terminal domains of dystrophin [23].
• The cysteine 3340 in the ZZ domain is essential for the binding of dystrophin to beta-dystroglycan [24].

Physical interactions of DMD

• Syntrophin binds to an alternatively spliced exon of dystrophin [16].
• The constructed evolutionary tree also implies that the vertebrate small and simple structured gene encoding a Dp71-like protein, called DRP2 , evolved from the dystrophin/utrophin ancestral large and complex gene by a duplication of only a small part of the gene [25].
• A beta-dystrobrevin antibody recognized a protein of the predicted size (71 kDa) that copurified with the dystrophin short form, Dp71 [26].
• These results suggest that an extremely short dystrophin lacking the entire actin-binding site in the N-terminus cannot function properly even if the protein possesses the putative DAG-binding cysteine-rich and the C-terminal domains, and still has an ability to associate with sarcolemmal membrane [27].
• The 2.0 A structure of the second calponin homology domain from the actin-binding region of the dystrophin homologue utrophin [28].

Enzymatic interactions of DMD

• The observation that a monoclonal antibody directed against epitopes within exons 73-74 (MANEX7374A) failed to detect this 58 kDa protein provides definitive evidence that Dp71 big up tri, open(110) is derived from Dp71 transcripts deleted for the syntrophin-binding domain [29].
• INTERPRETATION: The molecular mechanism of this subtype of X-linked cardiomyopathy may be explained by a conformational change in exon-29-deleted dystrophin, resulting in disruption of the sarcoglycan assembly in heart muscle but not skeletal muscle [30].

Co-localisations of DMD

• After insulin treatment, Hsp70 was mostly colocalized to the plasma membrane with dystrophin [31].
• CONCLUSIONS: Dystrophin partially colocalizes with costameric vinculin in normal and hypertrophied myocytes, a distribution lost in degenerating cells [32].

Regulatory relationships of DMD

• On Western blot, utrophin bands with concentrations 2- to 10-fold greater than in normal controls were detected in all DMD/BMD patients [33].
• Thus, we attempted to study whether or not a decrease of dystrophin expression would induce a modification in nNOS expression in cultured human neurons [34].
• We have used the polymerase chain reaction to see whether any of these exons are used alternatively in the different tissues that express dystrophin [35].
• Transient transfection experiments show that YY1 negatively regulates dystrophin transcription in C2C12 muscle cells [36].
• Caveolin-3 and dystrophin were expressed on the vacuolar membranes in lysosomal glycogen storage disease with normal acid maltase, hypokalemic myopathy, and centronuclear myopathy [37].

Other interactions of DMD

• We expressed the cDNA of human beta 1-syntrophin and the COOH terminus of human dystrophin in reticulocyte lysates using an in vitro transcription/translation system [16].
• Thus, like alpha-dystrobrevin, beta-dystrobrevin is likely to associate directly with dystrophin. alpha- and beta-dystrobrevins failed to copurify with each other, however [26].
• We examined whether the dystrophin-associated glycoprotein complex (GPC), which serves to fix dystrophin to cell membranes, is present at the sarcolemma in Duchenne muscular dystrophy (DMD) muscles using an immunohistochemical method [38].
• The decreased expression of dystrophin may indicate a loss of polarity in the distribution of AQP-4 in astrocytes [39].
• In sharp contrast to skeletal muscle, however, full-size dystrophin and 50DAG were undetectable in peripheral nerve [40].

Analytical, diagnostic and therapeutic context of DMD

• CONCLUSIONS: These results suggest that iNOS could play a role in the physiopathology of DMD and that the abnormal expression of iNOS could be corrected by gene therapy [19].
• Together these animal models have led to a delineation of protein functions and localization patterns that will be useful for the generation of potential therapies for DMD [41].
• Sequence analysis of the entire cDNA for the autosomal dystrophin-related protein utrophin has shown that dystrophin and utrophin are closely related [20].
• Ribonuclease protection and PCR assays demonstrated a reduction in muscle promoter transcribed dystrophin mRNA in the heart compared to skeletal muscle [5].
• A deficiency of cardiac dystrophin protein was observed by Western blot and lack of membrane localization by immunocytochemistry [5].

References