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.

Control of mitochondrial integrity in ageing and disease

“…Remarkably, the lifespan extension phenotype can be reverted by the expression of the human CLPP gene indicating a strong functional conservation of the fungal and the human protease. In humans, recessive CLPP mutations were observed in the Perrault variant of ovarian failure and sensorineural hearing loss [139]. In an independent study, the disease has been faithfully recapitulated in a mouse model that enabled detailed molecular and phenotypic studies [197].…”

Exome analysis identified a novel missense mutation in the CLPP gene in a consanguineous Saudi family expanding the clinical spectrum of Perrault Syndrome type-3

“…Mutations in the mitochondrial histidyl-tRNA synthetase (HARS2, OMIM 600783) gene on chromosome 5q31.3 cause PRLTS2 because of the reduction of HARS2 enzyme activity, which leads to defective mitochondrial protein synthesis and results in mammalian gonadal dysgenesis [11]. PRLTS type-3 (PRLTS3, OMIM 614129) patients are characterized by progressive hearing loss, female infertility and premature menopause secondary to ovarian dysgenesis, microcephaly, epilepsy, and growth and mental retardation because of pathogenic variations in the caseinolytic mitochondrial matrix peptidase proteolytic subunit (CLPP, OMIM 601119) gene on chromosome 19p13.3 [12].…”

Mitochondrial unfolded protein response gene Clpp is required to maintain ovarian follicular reserve during aging, for oocyte competence, and development of pre‐implantation embryos

“…Transcriptional activation of mtUPR genes and translational suppression seem to be mediated by two parallel mechanisms, both requiring CLPP (Aldridge et al., 2007; Benedetti et al., 2006; Haynes et al., 2007; Zhao et al., 2002) and reviewed in (Jensen & Jasper, 2014; Schulz & Haynes, 2015). It is important that, recessive Clpp mutations have been identified in the human Perrault variant of ovarian failure and sensorineural hearing loss (Jenkinson et al., 2013), and global germline Clpp knockout mice display auditory deficits and complete female and male infertility, in addition to reduced pre/postnatal survival and marked ubiquitous growth retardation (Gispert et al., 2013). …”