2. Academic Validation
  3. Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease

Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease

  • Am J Hum Genet. 2013 Apr 4;92(4):605-13. doi: 10.1016/j.ajhg.2013.02.013.
Emma M Jenkinson 1,  Atteeq U Rehman,  Tom Walsh,  Jill Clayton-Smith,  Kwanghyuk Lee,  Robert J Morell,  Meghan C Drummond,  Shaheen N Khan,  Muhammad Asif Naeem,  Bushra Rauf,  Neil Billington,  Julie M Schultz,  Jill E Urquhart,  Ming K Lee,  Andrew Berry,  Neil A Hanley,  Sarju Mehta,  Deirdre Cilliers,  Peter E Clayton,  Helen Kingston,  Miriam J Smith,  Thomas T Warner,  University of Washington Center for Mendelian Genomics,  Graeme C Black,  Dorothy Trump,  Julian R E Davis,  Wasim Ahmad,  Suzanne M Leal,  Sheikh Riazuddin,  Mary-Claire King,  Thomas B Friedman,  William G Newman
Affiliations

Affiliation

  • 1 Centre for Genetic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust as part of Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
PMID: 23541340 DOI: 10.1016/j.ajhg.2013.02.013
Abstract

Perrault syndrome is a genetically and clinically heterogeneous autosomal-recessive condition characterized by sensorineural hearing loss and ovarian failure. By a combination of linkage analysis, homozygosity mapping, and exome Sequencing in three families, we identified mutations in ClpP as the likely cause of this phenotype. In each family, affected individuals were homozygous for a different pathogenic ClpP allele: c.433A>C (p.Thr145Pro), c.440G>C (p.Cys147Ser), or an experimentally demonstrated splice-donor-site mutation, c.270+4A>G. ClpP, a component of a mitochondrial ATP-dependent proteolytic complex, is a highly conserved endopeptidase encoded by ClpP and forms an element of the evolutionarily ancient mitochondrial unfolded-protein response (UPR(mt)) stress signaling pathway. Crystal-structure modeling suggests that both substitutions would alter the structure of the ClpP barrel chamber that captures unfolded proteins and exposes them to proteolysis. Together with the previous identification of mutations in HARS2, encoding mitochondrial histidyl-tRNA synthetase, mutations in ClpP expose dysfunction of mitochondrial protein homeostasis as a cause of Perrault syndrome.

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