title: Novel sequence variants in dysferlin-deficient muscular dystrophy leading to mRNA decay and possible C2-domain misfolding.
abstract: Mutations in the gene encoding dysferlin (DYSF) cause the allelic autosomal recessive disorders limb girdle muscular dystrophy 2B and Miyoshi myopathy. It encompasses 55 exons spanning 150 kb of genomic DNA. Dysferlin is involved in membrane repair in skeletal muscle. We identified three families with novel sequence variants in DYSF. All affected family members showed limb girdle weakness and had reduced or absent dysferlin protein on immunohistochemistry. All exons of DYSF were screened by genomic sequencing. Five novel variants in DYSF were found: two missense mutations (c.895G>A and c.4022T>C), one 5' donor splice-site variant (c.855+1delG), one nonsense mutation (c.1448C>A), and a variant in the 3'UTR of DYSF (c.*107T>A). All alterations were confirmed by restriction enzyme analysis and not found in 400 control alleles. Nonsense mediated RNA decay or changes in the three-dimensional protein structure resulting in intracellular dysferlin aggregates and finally the lack of dysferlin protein were identified as consequences of the novel DYSF variants.
authors.affiliation: Department of Cardiology, Franz Volhard Clinic, Helios Clinic, Berlin, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Wenzel
authors.forename: Miriam
authors.initials: M
authors.lastname: Carl
authors.forename: Andreas
authors.initials: A
authors.lastname: Perrot
authors.forename: Joanna
authors.initials: J
authors.lastname: Zabojszcza
authors.forename: Maziar
authors.initials: M
authors.lastname: Assadi
authors.forename: Martin
authors.initials: M
authors.lastname: Ebeling
authors.forename: Christian
authors.initials: C
authors.lastname: Geier
authors.forename: Peter N
authors.initials: PN
authors.lastname: Robinson
authors.forename: Wolfram
authors.initials: W
authors.lastname: Kress
authors.forename: Karl-Josef
authors.initials: KJ
authors.lastname: Osterziel
authors.forename: Simone
authors.initials: S
authors.lastname: Spuler
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D004252:DNA Mutational Analysis; D000073939:Dysferlin; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology; D009136:Muscular Dystrophies / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D022821:RNA Splice Sites; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins; D022821:RNA Splice Sites; D012333:RNA, Messenger