ZFIN ID: ZDB-PUB-120730-12
Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy
Sarparanta, J., Jonson, P.H., Golzio, C., Sandell S, Luque, H., Screen, M., McDonald, K., Stajich, J.M., Mahjneh, I., Vihola, A., Raheem, O., Penttilä, S., Lehtinen, S., Huovinen, S., Palmio, J., Tasca, G., Ricci, E., Hackman, P., Hauser, M., Katsanis, N., and Udd, B.
Date: 2012
Source: Nature Genetics   44(4): 450-455 (Journal)
Registered Authors: Katsanis, Nicholas
Keywords: none
MeSH Terms:
  • Adaptor Proteins, Signal Transducing/genetics
  • Adaptor Proteins, Signal Transducing/metabolism
  • Animals
  • Apoptosis Regulatory Proteins
  • Finland
  • Genotype
  • HSP40 Heat-Shock Proteins/genetics*
  • HSP40 Heat-Shock Proteins/metabolism
  • Humans
  • Italy
  • Molecular Chaperones/genetics*
  • Molecular Chaperones/metabolism
  • Muscle, Skeletal/metabolism
  • Muscle, Skeletal/pathology
  • Muscular Dystrophies, Limb-Girdle/genetics*
  • Muscular Dystrophies, Limb-Girdle/metabolism*
  • Muscular Dystrophies, Limb-Girdle/pathology
  • Mutation, Missense
  • Nerve Tissue Proteins/genetics*
  • Nerve Tissue Proteins/metabolism
  • United States
  • Zebrafish/embryology
  • Zebrafish/genetics
PubMed: 22366786 Full text @ Nat. Genet.

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.