Proteasome subunit PSMC3 variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress

EMBO Mol Med. 2020 Jul 7;12(7):e11861. doi: 10.15252/emmm.201911861. Epub 2020 Jun 5.


The ubiquitin-proteasome system degrades ubiquitin-modified proteins to maintain protein homeostasis and to control signalling. Whole-genome sequencing of patients with severe deafness and early-onset cataracts as part of a neurological, sensorial and cutaneous novel syndrome identified a unique deep intronic homozygous variant in the PSMC3 gene, encoding the proteasome ATPase subunit Rpt5, which lead to the transcription of a cryptic exon. The proteasome content and activity in patient's fibroblasts was however unaffected. Nevertheless, patient's cells exhibited impaired protein homeostasis characterized by accumulation of ubiquitinated proteins suggesting severe proteotoxic stress. Indeed, the TCF11/Nrf1 transcriptional pathway allowing proteasome recovery after proteasome inhibition is permanently activated in the patient's fibroblasts. Upon chemical proteasome inhibition, this pathway was however impaired in patient's cells, which were unable to compensate for proteotoxic stress although a higher proteasome content and activity. Zebrafish modelling for knockout in PSMC3 remarkably reproduced the human phenotype with inner ear development anomalies as well as cataracts, suggesting that Rpt5 plays a major role in inner ear, lens and central nervous system development.

Keywords: PSMC3; cataract; deafness; neurosensory disease; proteasome.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / genetics*
  • Adolescent
  • Animals
  • Cataract / genetics*
  • Cataract / pathology
  • Child
  • Child, Preschool
  • Consanguinity
  • Deafness / genetics*
  • Deafness / physiopathology
  • Female
  • Humans
  • Infant
  • Male
  • Mutation*
  • Nuclear Respiratory Factor 1 / genetics
  • Pedigree
  • Phenotype
  • Proteasome Endopeptidase Complex / genetics*
  • Proteasome Inhibitors / pharmacology
  • Proteolysis* / drug effects
  • Stress, Physiological* / drug effects
  • Stress, Physiological* / genetics
  • Syndrome
  • Ubiquitin / metabolism
  • Zebrafish / genetics
  • Zebrafish Proteins / genetics*


  • NRF1 protein, human
  • Nuclear Respiratory Factor 1
  • Proteasome Inhibitors
  • Ubiquitin
  • Zebrafish Proteins
  • Proteasome Endopeptidase Complex
  • ATPases Associated with Diverse Cellular Activities
  • PSMC3 protein, human
  • psmc3 protein, zebrafish