Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy

Enzo Ricci, Giorgio Tasca, J Sarparanta, Ph Jonson, C Golzio, S Sandell, H Luque, M Screen, K Mcdonald, Jm Stajich, I Mahjneh, A Vihola, O Raheem, S Penttilä, S Lehtinen, S Huovinen, J Palmio, P Hackman, M Hauser, N KatsanisB. Udd

Risultato della ricerca: Contributo in rivistaArticolo in rivista

164 Citazioni (Scopus)


Limb-girdle muscular dystrophy type 1D (LGMD1D) was linked to chromosome 7q36 over a decade ago, but its genetic cause has remained elusive. Here we studied nine LGMD-affected families from Finland, the United States and Italy and identified four dominant missense mutations leading to p.Phe93Leu or p.Phe89Ile changes in the ubiquitously expressed co-chaperone DNAJB6. Functional testing in vivo showed that the mutations have a dominant toxic effect mediated specifically by the cytoplasmic isoform of DNAJB6. In vitro studies demonstrated that the mutations increase the half-life of DNAJB6, extending this effect to the wild-type protein, and reduce its protective anti-aggregation effect. Further, we show that DNAJB6 interacts with members of the CASA complex, including the myofibrillar myopathy-causing protein BAG3. Our data identify the genetic cause of LGMD1D, suggest that its pathogenesis is mediated by defective chaperone function and highlight how mutations in a ubiquitously expressed gene can exert effects in a tissue-, isoform- and cellular compartment-specific manner.
Lingua originaleEnglish
pagine (da-a)450-455
Numero di pagine6
RivistaNature Genetics
Stato di pubblicazionePubblicato - 2012


  • Adaptor Proteins, Signal Transducing
  • Animals
  • Finland
  • Genotype
  • HSP40 Heat-Shock Proteins
  • Humans
  • Italy
  • Molecular Chaperones
  • Muscle, Skeletal
  • Muscular Dystrophies, Limb-Girdle
  • Mutation, Missense
  • Nerve Tissue Proteins
  • United States
  • Zebrafish


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