Genetic suppression of phenotypes arising from mutations in dystrophin-related genes in Caenorhabditis elegans.
BACKGROUND
Dystrophin is the product of the gene that is mutated in Duchenne muscular dystrophy (DMD), a progressive neuromuscular disease for which no treatment is available. Mice carrying a mutation in the gene for dystrophin (mdx mice) display only a mild phenotype, but it is aggravated when combined with a mutation in the MyoD gene. The nematode worm Caenorhabditis elegans has a dystrophin homologue (dys-1), but null mutations in dys-1 do not result in muscle degeneration.


RESULTS
We generated worms carrying both the dys-1 null mutation cx18, and a weak mutation, cc561ts, of the C. elegans MyoD homologue hlh-1. The double mutants displayed a time-dependent impairment of locomotion and egg laying, a phenotype not seen in the single mutants, and extensive muscle degeneration. This result allowed us to look for genes that, when misexpressed, could suppress the dys-1; hlh-1 phenotype. When overexpressed, the dyc-1 gene - whose loss-of-function phenotype resembles that of dys-1 - partially suppressed the dys-1; hlh-1 phenotype. The dyc-1 gene encodes a novel protein sharing similarities with the mammalian neural nitric oxide synthase (nNOS)-binding protein CAPON, and is expressed in the muscles of the worm.


CONCLUSIONS
As a C. elegans model for dystrophin-dependent myopathy, the dys-1; hlh-1 worms should permit the identification of genes, and ultimately drugs, that would reverse the muscle degeneration in this model.
Gieseler
K
K
CGMC, CNRS-UMR5534, Université Lyon-1, 43 boulevard du 11 Novembre, 69622, Villeurbanne cedex, France.
Grisoni
K
K
Ségalat
L
L
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000033:anatomy & histology / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics* / Q000502:physiology; D017930:Genes, Reporter; D015801:Helminth Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D009124:Muscle Proteins; D009132:Muscles / Q000473:pathology*; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000473:pathology; D016296:Mutagenesis; D018006:Myogenic Regulatory Factors; D009687:Nuclear Proteins; D010590:Phalloidine / Q000494:pharmacology; D010641:Phenotype; D051381:Rats; D016415:Sequence Alignment; D013489:Suppression, Genetic; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D016189:Dystrophin; D015801:Helminth Proteins; D009124:Muscle Proteins; D018006:Myogenic Regulatory Factors; C488082:NOS1AP protein, rat; C110667:Nos1ap protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; C406103:dys-1 protein, C elegans; C066645:HLH-1 protein, C elegans; D010590:Phalloidine