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

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.

• Authors: Emma M Jenkinson, 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
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 92 Issue 4 Pg. 605-13 (Apr 04 2013) ISSN: 1537-6605 [Electronic] United States
• PMID: 23541340 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Adenosine Triphosphate
• ATP-Dependent Proteases
• ClpP protein, human
• Endopeptidase Clp

Topics

• ATP-Dependent Proteases (genetics, metabolism)
• Adenosine Triphosphate (metabolism)
• Adolescent
• Adult
• Endopeptidase Clp (genetics)
• Exome (genetics)
• Female
• Genes, Recessive
• Gonadal Dysgenesis, 46,XX (etiology)
• Hearing Loss, Sensorineural (etiology)
• Homozygote
• Humans
• In Situ Hybridization
• Male
• Mitochondria (enzymology, genetics)
• Mutation (genetics)
• Pedigree
• Phenotype
• Young Adult