2. Academic Validation
  3. Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy

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

  • Nat Genet. 2012 Feb 26;44(4):450-5, S1-2. doi: 10.1038/ng.1103.
Jaakko Sarparanta 1,  Per Harald Jonson,  Christelle Golzio,  Satu Sandell,  Helena Luque,  Mark Screen,  Kristin McDonald,  Jeffrey M Stajich,  Ibrahim Mahjneh,  Anna Vihola,  Olayinka Raheem,  Sini Penttilä,  Sara Lehtinen,  Sanna Huovinen,  Johanna Palmio,  Giorgio Tasca,  Enzo Ricci,  Peter Hackman,  Michael Hauser,  Nicholas Katsanis,  Bjarne Udd
Affiliations

Affiliation

  • 1 Folkhälsan Institute of Genetics and Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
PMID: 22366786 DOI: 10.1038/ng.1103
Abstract

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.

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