Disease relevance of dystrophin

• Dystrobrevins are protein components of the dystrophin complex, whose disruption leads to Duchenne muscular dystrophy and related diseases [1].
• We show here that overexpression of the Dyb-1 protein delays the onset of the myopathy observed in the C. elegans double mutant (dys-1; hlh-1 mutations) [2].
• Here we show that dysferlin-null mice maintain a functional dystrophin-glycoprotein complex but nevertheless develop a progressive muscular dystrophy [3].

High impact information on dystrophin

• Here, we show that, in Caenorhabditis elegans, a gain-of-function mutation in the egl-19 calcium channel gene dramatically increases muscle degeneration in dystrophin mutants [4].
• The SLO-1 BK channel of Caenorhabditis elegans is critical for muscle function and is involved in dystrophin-dependent muscle dystrophy [5].
• Gene expression profiling studies on Caenorhabditis elegans dystrophin mutants dys-1(cx-35) and dys-1(cx18) [6].
• The Caenorhabditis elegans genome contains a single dystrophin/utrophin orthologue, dys-1 [6].
• Since Caenorhabditis elegans possesses a dystrophin-like gene (dys-1), we investigated whether homologues of the DGC members could also be found in the C. elegans genome [7].

Chemical compound and disease context of dystrophin

• Here, by using a Caenorhabditis elegans model of dystrophin-dependent muscular dystrophy, we show that the neurohormone serotonin and some of its agonists are potent suppressors of muscle degeneration [8].

Biological context of dystrophin

• Dystrobrevins are dystrophin-associated proteins potentially involved in signal transduction [2].
• Phenotypes similar to that of dys-1 were obtained, both in the wild-type background and in combination with other mutations [7].
• Using RNA interference and existing mutants, we genetically impaired the excitation-contraction cascade at specific points in a dystrophin-deficient C. elegans strain which normally undergoes extensive muscle degeneration [9].
• Based on reporter gene analysis and heterologous promoter expression, the site of action of the dys-1 gene seems to be in muscles [10].
• A chimeric transgene in which the C-terminal end of the protein has been replaced by the human dystrophin sequence is able to partly suppress the phenotype of the dys-1 mutants, showing that both proteins share some functional similarity [10].

Anatomical context of dystrophin

• Mutations in the human dystrophin gene cause Duchenne muscular dystrophy, a common neuromuscular disease leading to a progressive necrosis of muscle cells [10].
• In mammals, the lack of dystrophin leads to a degeneration of skeletal muscles [9].
• Thus, it is the physical tension exerted on the muscle fibers which is the key deleterious event in the absence of dystrophin [9].

Associations of dystrophin with chemical compounds

• Prednisone in dystrophin-deficient Caernorabditis elegans [11].
• SNF-6 is an acetylcholine transporter interacting with the dystrophin complex in Caenorhabditis elegans [12].
• Finally, the dys-1 mutants are hypersensitive to acetylcholine and to the acetylcholinesterase inhibitor aldicarb, suggesting that dys-1 mutations affect cholinergic transmission [10].

Physical interactions of dystrophin

• These results are consistent with a model according to which dystrobrevin must bind to dystrophin to be able to function properly [13].
• In mammals, the dystrophin-glycoprotein complex (DGC) includes dystrophin, as well as transmembrane and cytoplasmic proteins [7].

Other interactions of dystrophin

• These findings suggest that: (1) dystrobrevin and dystrophin are functionally related and (2) their disruption impairs cholinergic signalling [14].
• Therefore, in C. elegans, disruption of the dystrophin/utrophin-like dys-1 gene affects acetylcholinesterase activity [15].
• In addition, double mutants carrying a mutation in the dys-1 gene plus a mutation in either of the two major acetylcholinesterase genes (ace-1 and ace-2) display locomotor defects consistent with a strong reduction of acetylcholinesterases, whereas none of the single mutants does [15].

Analytical, diagnostic and therapeutic context of dystrophin

• The deletions affecting the second helix of the Dyb-1 coiled-coil domain abolished the binding of dystrobrevin to dystrophin both in vitro and in the two-hybrid assay [13].
• In the model animal Caenorhabditis elegans, mutations of the dys-1 dystrophin-like gene lead to a muscular degenerative phenotype when they are associated with a mild MyoD mutation [16].

References