Extension of the DNAJB2a isoform in a dominant neuromyopathy family

Jaakko Sarparanta, Per Harald Jonson, Jens Reimann, Anna Vihola, Helena Luque, Sini Penttilä, Mridul Johari, Marco Savarese, Peter Hackman, Cornelia Kornblum, Bjarne Udd

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

Sammanfattning

Recessive mutations in the DNAJB2 gene, encoding the J-domain co-chaperones DNAJB2a and DNAJB2b, have previously been reported as the genetic cause of progressive peripheral neuropathies, rarely involving pyramidal signs, parkinsonism and myopathy. We describe here a family with the first dominantly acting DNAJB2 mutation resulting in a late-onset neuromyopathy phenotype. The c.832 T > G p.(*278Glyext*83) mutation abolishes the stop codon of the DNAJB2a isoform resulting in a C-terminal extension of the protein, with no direct effect predicted on the DNAJB2b isoform of the protein. Analysis of the muscle biopsy showed reduction of both protein isoforms. In functional studies, the mutant protein mislocalized to the endoplasmic reticulum due to a transmembrane helix in the C-terminal extension. The mutant protein underwent rapid proteasomal degradation and also increased the turnover of co-expressed wild-type DNAJB2a, potentially explaining the reduced protein amount in the patient muscle tissue. In line with this dominant negative effect, both wild-type and mutant DNAJB2a were shown to form polydisperse oligomers.

Originalspråkengelska
TidskriftHuman Molecular Genetics
Volym32
Nummer21
Sidor (från-till)3029-3039
Antal sidor11
ISSN0964-6906
DOI
StatusPublicerad - 17 okt. 2023
MoE-publikationstypA1 Tidskriftsartikel-refererad

Bibliografisk information

Publisher Copyright:
© The Author(s) 2023. Published by Oxford University Press.

Vetenskapsgrenar

  • 1184 Genetik, utvecklingsbiologi, fysiologi
  • 3124 Neurologi och psykiatri

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