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

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Abstrakti

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.

Alkuperäiskielienglanti
LehtiHuman Molecular Genetics
Vuosikerta32
Numero21
Sivut3029-3039
Sivumäärä11
ISSN0964-6906
DOI - pysyväislinkit
TilaJulkaistu - 17 lokak. 2023
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Lisätietoja

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

Tieteenalat

  • 1184 Genetiikka, kehitysbiologia, fysiologia
  • 3124 Neurologia ja psykiatria

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