title: Exome sequencing reveals DNAJB6 mutations in dominantly-inherited myopathy.
abstract: OBJECTIVE
  To identify the causative gene in an autosomal dominant limb-girdle muscular dystrophy (LGMD) with skeletal muscle vacuoles.
  
  
  METHODS
  Exome sequencing was used to identify candidate mutations in the studied pedigree. Genome-wide linkage was then used to narrow the list of candidates to a single disease-associated mutation. Additional pedigrees with dominant or sporadic myopathy were screened for mutations in the same gene (DNAJB6) using exome sequencing. Skeletal muscle from affected patients was evaluated with histochemistry and immunohistochemical stains for dystrophy-related proteins, SMI-31, TDP43, and DNAJB6.
  
  
  RESULTS
  Exome analysis in 3 affected individuals from a family with dominant LGMD and vacuolar pathology identified novel candidate mutations in 22 genes. Linkage analysis excluded all variants except a Phe93Leu mutation in the G/F domain of the DNAJB6 gene, which resides within the LGMD locus at 7q36. Analysis of exome sequencing data from other pedigrees with dominant myopathy identified a second G/F domain mutation (Pro96Arg) in DNAJB6. Affected muscle showed mild dystrophic changes, vacuoles, and abnormal aggregation of proteins, including TDP-43 and DNAJB6 itself.
  
  
  CONCLUSIONS
  Mutations within the G/F domain of DNAJB6 are a novel cause of dominantly-inherited myopathy. DNAJB6 is a member of the HSP40/DNAJ family of molecular co-chaperones tasked with protecting client proteins from irreversible aggregation during protein synthesis or during times of cellular stress. The abnormal accumulation of several proteins in patient muscle, including DNAJB6 itself, suggest that DNAJB6 function is compromised by the identified G/F domain mutations.
authors.affiliation: Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Harms
authors.forename: R Brian
authors.initials: RB
authors.lastname: Sommerville
authors.forename: Peggy
authors.initials: P
authors.lastname: Allred
authors.forename: Shaughn
authors.initials: S
authors.lastname: Bell
authors.forename: Duanduan
authors.initials: D
authors.lastname: Ma
authors.forename: Paul
authors.initials: P
authors.lastname: Cooper
authors.forename: Glenn
authors.initials: G
authors.lastname: Lopate
authors.forename: Alan
authors.initials: A
authors.lastname: Pestronk
authors.forename: Conrad C
authors.initials: CC
authors.lastname: Weihl
authors.forename: Robert H
authors.initials: RH
authors.lastname: Baloh
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001120:Arginine / Q000235:genetics; D059472:Exome / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D055106:Genome-Wide Association Study / Q000379:methods; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics*; D008969:Molecular Sequence Data; D009135:Muscular Diseases / Q000175:diagnosis / Q000235:genetics*; D049288:Muscular Dystrophies, Limb-Girdle / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D011392:Proline / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods; D055815:Young Adult
chemical_list: C485565:DNAJB6 protein, human; D050956:HSP40 Heat-Shock Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D001120:Arginine; D011392:Proline