title: Diagnostically important muscle pathology in DNAJB6 mutated LGMD1D.
abstract: BACKGROUND
  Limb girdle muscular dystrophies are a large group of both dominantly and recessively inherited muscle diseases. LGMD1D is caused by mutated DNAJB6 and the molecular pathogenesis is mediated by defective chaperonal function leading to impaired handling of misfolded proteins which normally would be degraded. Here we aim to clarify muscle pathology of LGMD1D in order to facilitate diagnostic accuracy. After following six Finnish LGMD1D families, we analysed 21 muscle biopsies obtained from 15 patients at different time points after the onset of symptoms. All biopsies were obtained from the lower limb muscles and processed for routine histochemistry, extensive immunohistochemistry and electron microscopy.
  
  
  RESULTS
  Histopathological findings were myopathic or dystrophic combined with rimmed vacuolar pathology, and small myofibrillar aggregates. These myofibrillar inclusions contained abnormal accumulation of a number of proteins such as myotilin, αB-crystallin and desmin on immunohistochemistry, and showed extensive myofibrillar disorganization with excess of Z-disk material on ultrastructure. Later in the disease process the rimmed vacuolar pathology dominated with rare cases of pronounced larger pleomorphic myofibrillar aggregates. The rimmed vacuoles were reactive for several markers of defect autophagy such as ubiquitin, TDP-43, p62 and SMI-31.
  
  
  CONCLUSIONS
  Since DNAJB6 is known to interact with members of the chaperone assisted selective autophagy complex (CASA), including BAG3 - a known myofibrillar myopathy causing gene, the molecular muscle pathology is apparently mediated through impaired functions of CASA and possibly other complexes needed for the maintenance of the Z-disk and sarcomeric structures. The corresponding findings on histopathology offer clues for the diagnosis.
authors: Department of Neurology, Seinäjoki Central Hospital, Seinäjoki, Finland. satu.sandell@epshp.fi.|Department of Neurology, Tampere University Hospital, Tampere, Finland. satu.sandell@epshp.fi.|Neuromuscular Research Center, Tampere University Hospital, University of Tampere, Tampere, Finland. satu.sandell@epshp.fi.
authors: Satu
authors: S
authors: Sandell
authors: Neuromuscular Research Center, Tampere University Hospital, University of Tampere, Tampere, Finland.|Department of Pathology, Fimlab Laboratories, Tampere University Hospital, University of Tampere, Tampere, Finland.
authors: Sanna
authors: S
authors: Huovinen
authors: Department of Neurology, Tampere University Hospital, Tampere, Finland.|Neuromuscular Research Center, Tampere University Hospital, University of Tampere, Tampere, Finland.
authors: Johanna
authors: J
authors: Palmio
authors: Neuromuscular Research Center, Tampere University Hospital, University of Tampere, Tampere, Finland.|Department of Pathology and Genetics, HUSLAB Laboratories, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
authors: Olayinka
authors: O
authors: Raheem
authors: Neuromuscular Research Center, Tampere University Hospital, University of Tampere, Tampere, Finland.
authors: Mikaela
authors: M
authors: Lindfors
authors: Department of Pathology and Genetics, HUSLAB Laboratories, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
authors: Fang
authors: F
authors: Zhao
authors: Neuromuscular Research Center, Tampere University Hospital, University of Tampere, Tampere, Finland.|Department of Pathology, Fimlab Laboratories, Tampere University Hospital, University of Tampere, Tampere, Finland.
authors: Hannu
authors: H
authors: Haapasalo
authors: Department of Neurology, Tampere University Hospital, Tampere, Finland.|Neuromuscular Research Center, Tampere University Hospital, University of Tampere, Tampere, Finland.|Department of Medical Genetics, Folkhälsan Institute of Genetics, University of Helsinki, Helsinki, Finland.|Department of Neurology, Vaasa Central Hospital, Vaasa, Finland.
authors: Bjarne
authors: B
authors: Udd
mesh_terms: D000328:Adult; D005192:Family Health; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics*; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D049288:Muscular Dystrophies, Limb-Girdle / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: C485565:DNAJB6 protein, human; D050956:HSP40 Heat-Shock Proteins; D018832:Molecular Chaperones; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins