Related resources
Full-text held externally
- PMID: 23541340
- UKPMCID: 23541340
- DOI: 10.1016/j.ajhg.2013.02.013
Search for item elsewhere
University researcher(s)
Academic department(s)
Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease.
Jenkinson, Emma M; Rehman, Atteeq U; Walsh, Tom; Clayton-Smith, Jill; Lee, Kwanghyuk; Morell, Robert J; Drummond, Meghan C; Khan, Shaheen N; Naeem, Muhammad Asif; Rauf, Bushra; Billington, Neil; Schultz, Julie M; Urquhart, Jill E; Lee, Ming K; Berry, Andrew; Hanley, Neil A; Mehta, Sarju; Cilliers, Deirdre; Clayton, Peter E; Kingston, Helen; Smith, Miriam J; Warner, Thomas T; ; Black, Graeme C; Trump, Dorothy; Davis, Julian R E; Ahmad, Wasim; Leal, Suzanne M; Riazuddin, Sheikh; King, Mary-Claire; Friedman, Thomas B; Newman, William G
American journal of human genetics. 2013;92(4):605-13.
Access to files
Full-text and supplementary files are not available from Manchester eScholar. Full-text is available externally using the following links:
Full-text held externally
- PMID: 23541340
- UKPMCID: 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.
Bibliographic metadata
- Jenkinson, Emma M
- Rehman, Atteeq U
- Walsh, Tom
- Clayton-Smith, Jill
- Lee, Kwanghyuk
- Morell, Robert J
- Drummond, Meghan C
- Khan, Shaheen N
- Naeem, Muhammad Asif
- Rauf, Bushra
- Billington, Neil
- Schultz, Julie M
- Urquhart, Jill E
- Lee, Ming K
- Berry, Andrew
- Hanley, Neil A
- Mehta, Sarju
- Cilliers, Deirdre
- Clayton, Peter E
- Kingston, Helen
- Smith, Miriam J
- Warner, Thomas T
- Black, Graeme C
- Trump, Dorothy
- Davis, Julian R E
- Ahmad, Wasim
- Leal, Suzanne M
- Riazuddin, Sheikh
- King, Mary-Claire
- Friedman, Thomas B
- Newman, William G
- DC000039-15, NIDCD NIH HHS, United States
- HL004232, NHLBI NIH HHS, United States
- N01 HG065403, NHGRI NIH HHS, United States
- N01-HG-65403, NHGRI NIH HHS, United States
- R01 DC003594, NIDCD NIH HHS, United States
- R01 DC005641, NIDCD NIH HHS, United States
- R01 DC011651, NIDCD NIH HHS, United States
- U54 HG006493, NHGRI NIH HHS, United States
- , Wellcome Trust, United Kingdom