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

作者：Sarparanta Jaakko; Jonson Per Harald; Golzio Christelle; Sandell Satu; Luque Helena; Screen Mark; McDonald Kristin; Stajich Jeffrey M; Mahjneh Ibrahim; Vihola Anna; Raheem Olayinka; Penttila Sini; Lehtinen Sara; Huovinen Sanna; Palmio Johanna; Tasca Giorgio; Ricci Enzo; Hackman Peter; Hauser Michael; Katsanis Nicholas; Udd Bjarne^*

来源：Nature Genetics, 2012, 44(4): 450-U136.

DOI：10.1038/ng.1103

Limb-girdle muscular dystrophy type 1D (LGMD1D) was linked to chromosome 7q36 over a decade ago(1), 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.

• 出版日期2012-4