title: Mutation impact on dysferlin inferred from database analysis and computer-based structural predictions.
abstract: Dysferlin is a large sarcolemmal protein implicated in the repair of surface membrane tears in muscle cells. Mutations in dysferlin result in limb girdle muscular dystrophy type 2B and Miyoshi myopathy. Using a cDNA based approach we identified eight new pathogenic dysferlin alleles. To better understand how missense mutations could lead to reduced or absent dysferlin expression levels, we mapped missense mutations from our own and from published databases (n=55) to the secondary protein structure of dysferlin, deduced by computerized structural prediction tools. We found the protein to be very sensitive to the alteration of residues that were predicted to be buried inside the protein structure. We identified seven putative C2 domains, one more than commonly reported, of both type I and type II topology in dysferlin. Missense mutations often affected those structures as well as residues that were highly conserved between members of the ferlin family. Thus, alteration of structurally important residues in dysferlin could lead to improper folding and degradation of the mutant protein.
authors.affiliation: Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec Canada H3A 2B4.
authors.forename: Christian
authors.initials: C
authors.lastname: Therrien
authors.forename: Dubravka
authors.initials: D
authors.lastname: Dodig
authors.forename: George
authors.initials: G
authors.lastname: Karpati
authors.forename: Michael
authors.initials: M
authors.lastname: Sinnreich
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence / Q000235:genetics; D002648:Child; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000032:analysis; D000073939:Dysferlin; D019143:Evolution, Molecular; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics*; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry* / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D020125:Mutation, Missense / Q000235:genetics*; D010802:Phylogeny; D017510:Protein Folding; D020836:Protein Structure, Quaternary / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D040901:Proteomics
chemical_list: D018076:DNA, Complementary; C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins