Perrault syndrome type 3 caused by diverse molecular defects in CLPP

Sci Rep. 2018 Aug 27;8(1):12862. doi: 10.1038/s41598-018-30311-1.


The maintenance of mitochondrial protein homeostasis (proteostasis) is crucial for correct cellular function. Recently, several mutations in the mitochondrial protease CLPP have been identified in patients with Perrault syndrome 3 (PRLTS3). These mutations can be arranged into two groups, those that cluster near the docking site (hydrophobic pocket, Hp) for the cognate unfoldase CLPX (i.e. T145P and C147S) and those that are adjacent to the active site of the peptidase (i.e. Y229D). Here we report the biochemical consequence of mutations in both regions. The Y229D mutant not only inhibited CLPP-peptidase activity, but unexpectedly also prevented CLPX-docking, thereby blocking the turnover of both peptide and protein substrates. In contrast, Hp mutations cause a range of biochemical defects in CLPP, from no observable change to CLPP activity for the C147S mutant, to dramatic disruption of most activities for the "gain-of-function" mutant T145P - including loss of oligomeric assembly and enhanced peptidase activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Endopeptidase Clp / chemistry
  • Endopeptidase Clp / genetics*
  • Endopeptidase Clp / metabolism
  • Genetic Association Studies*
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Gonadal Dysgenesis, 46,XX / diagnosis*
  • Gonadal Dysgenesis, 46,XX / genetics*
  • Gonadal Dysgenesis, 46,XX / metabolism
  • Hearing Loss, Sensorineural / diagnosis*
  • Hearing Loss, Sensorineural / genetics*
  • Hearing Loss, Sensorineural / metabolism
  • Humans
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Models, Molecular
  • Mutation
  • Protein Conformation


  • ClpP protein, human
  • Endopeptidase Clp
  • CLPX protein, human

Supplementary concepts

  • Gonadal dysgenesis XX type deafness