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 (UPRmt) 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.
| Original language | English |
|---|---|
| Pages (from-to) | 605-613 |
| Number of pages | 9 |
| Journal | American Journal of Human Genetics |
| Volume | 92 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 4 Apr 2013 |
Bibliographical note
Funding Information:We thank the families for their participation in the study. We thank Inna Belyantseva, Dennis Drayna, and Andrew J. Griffith for their critique of this manuscript. This study was supported by the Infertility Research Trust; by the Manchester University Biomedical Research Centre; by the Wellcome Trust (N.A.H. is a Senior Fellow in Clinical Science); by National Institutes of Health (NIH) grants and contracts R01 DC005641, R01 DC011651, R01 DC003594, N01 HG065403, and U54 HG006493; by the Higher Education Commission and the Ministry of Science and Technology of Pakistan; and by the International Center for Genetic Engineering and Biotechnology, Trieste, Italy (CRP/PAK08-01 contract 08/009 to Sh.R). Genotyping of family DEM4395 was performed at the Center for Inherited Disease Research, which is funded through the NIH to The Johns Hopkins University (contract number N01-HG-65403). N.B. was supported by National Heart, Lung, and Blood Institute (NIH) intramural funds (HL004232) to James Sellers. Work at the National Institute on Deafness and Other Communication Disorders (NIH) was supported by intramural funds (DC000039-15) to T.B.F. The authors also acknowledge GeneMANIA, the development of which was funded by Genome Canada through the Ontario Genomics Institute (2007-OGI-TD-05) and which is now funded by the Ontario Ministry of Research and Innovation.
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)