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

Jaakko Sarparanta, 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, Elias Nicholas KatsanisBjarne Udd*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

148 Scopus citations

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 myopathyg-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 compartmentg-specific manner.

Original languageEnglish (US)
Pages (from-to)450-455
Number of pages6
JournalNature Genetics
Volume44
Issue number4
DOIs
StatePublished - Apr 2012

ASJC Scopus subject areas

  • Genetics

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