title: Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy.
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.
authors.affiliation: Folkhälsan Institute of Genetics and Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Sarparanta
authors.forename: Per Harald
authors.initials: PH
authors.lastname: Jonson
authors.forename: Christelle
authors.initials: C
authors.lastname: Golzio
authors.forename: Satu
authors.initials: S
authors.lastname: Sandell
authors.forename: Helena
authors.initials: H
authors.lastname: Luque
authors.forename: Mark
authors.initials: M
authors.lastname: Screen
authors.forename: Kristin
authors.initials: K
authors.lastname: McDonald
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Stajich
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Mahjneh
authors.forename: Anna
authors.initials: A
authors.lastname: Vihola
authors.forename: Olayinka
authors.initials: O
authors.lastname: Raheem
authors.forename: Sini
authors.initials: S
authors.lastname: Penttilä
authors.forename: Sara
authors.initials: S
authors.lastname: Lehtinen
authors.forename: Sanna
authors.initials: S
authors.lastname: Huovinen
authors.forename: Johanna
authors.initials: J
authors.lastname: Palmio
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tasca
authors.forename: Enzo
authors.initials: E
authors.lastname: Ricci
authors.forename: Peter
authors.initials: P
authors.lastname: Hackman
authors.forename: Michael
authors.initials: M
authors.lastname: Hauser
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Bjarne
authors.initials: B
authors.lastname: Udd
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D005387:Finland; D005838:Genotype; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007558:Italy; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D014481:United States; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; C485565:DNAJB6 protein, human; D050956:HSP40 Heat-Shock Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins