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Biallelic pathogenic variants in CLPP, encoding the mitochondrial ATP‑dependent peptidase ClpP, are robustly associated with Perrault syndrome type 3, a form of Perrault syndrome characterized by sensorineural hearing loss in both sexes and premature ovarian insufficiency or ovarian dysgenesis in 46,XX females. The overall strength of the gene–disease association meets ClinGen “Definitive” criteria. Multiple unrelated families from diverse populations (Saudi, Turkish, Iranian, European, Chinese, Pakistani) have been reported with segregating biallelic CLPP variants and a consistent Perrault phenotype, beginning with three linkage‑mapped families in which homozygous CLPP variants were shown to underlie Perrault syndrome with sensorineural deafness and ovarian failure PMID:23541340. Subsequent cohort and genotype‑phenotype studies, together with functional analyses of specific variants, provide strong, mutually supportive evidence over more than 10 years PMID:25956234, PMID:27087618, PMID:27650058, PMID:26970254, PMID:32399598, PMID:34338890, PMID:39847269, PMID:40410890, PMID:30150665.
Perrault syndrome type 3 due to CLPP is inherited in an autosomal recessive manner. Core features are bilateral sensorineural hearing loss (typically congenital or early‑childhood and moderate‑to‑profound), and female gonadal dysfunction (primary ovarian insufficiency, ovarian dysgenesis, secondary amenorrhea). Neurologic involvement is common but variable, including ataxia, spasticity, peripheral neuropathy, seizures, developmental delay, intellectual disability, and brain atrophy PMID:23541340, PMID:25956234, PMID:39847269, PMID:40410890. Disease severity ranges from “classic” Perrault syndrome with normal cognition to severe neurodevelopmental disease with regression.
Across the curated literature, at least eight independent CLPP‑related Perrault families are directly documented, with several more summarized in review and cohort work. The initial linkage/exome study identified three consanguineous families, each with different homozygous pathogenic alleles: c.433A>C (p.Thr145Pro), c.440G>C (p.Cys147Ser), and c.270+4A>G, all segregating fully with disease and absent (or extremely rare) from population controls PMID:23541340. Subsequent single‑family reports describe a consanguineous Saudi pedigree with early‑onset severe hearing loss, regression, brain atrophy, and spasticity, in which genome‑wide homozygosity mapping and exome sequencing identified a novel homozygous CLPP exon 6 missense variant consistent with PRLTS3 PMID:25956234, and a Turkish family with two affected siblings showing bilateral sensorineural hearing loss and, in the female, secondary amenorrhea and gonadal dysgenesis, carrying a homozygous missense variant c.624C>G (p.Ile208Met) PMID:27087618. An Iranian family (Family A) with three affected offspring with congenital severe‑to‑profound hearing loss, ataxia, epilepsy, and intellectual disability carries compound heterozygous CLPP variants c.21del (p.Ala10ProfsTer?) and c.512C>G (p.Pro171Arg), identified by exome sequencing PMID:39847269.
Multi‑patient and genomic sequencing cohorts further substantiate the association. In a 14‑family Perrault series, one proband had homozygous CLPP mutations identified by targeted next‑generation sequencing, with segregation confirming autosomal recessive inheritance PMID:27650058. In a cohort of seven individuals from five families, CLPP and LARS2 variants were among the confirmed molecular diagnoses; biallelic CLPP variants were shown to cause Perrault syndrome with sensorineural hearing loss and ovarian insufficiency PMID:32399598. A more recent Han Chinese genotype‑phenotype study identified two unrelated Perrault type 3 pedigrees: one with compound heterozygous variants c.270+?C (splice) and c.355A>C (p.Ile119Leu), and another with c.400G>C (p.Asp134His) plus a large CLPP deletion, all segregating with disease PMID:40410890. A broader review summarizing CLPP‑associated Perrault syndrome collated 33 affected individuals, noting that 97% had hearing loss and 71% of females had primary ovarian insufficiency, and catalogued 21 pathogenic CLPP variants, 57% missense and 43% truncating PMID:40410890.
Segregation evidence is strong. Multiple consanguineous families demonstrate homozygous variants in all affected individuals with both obligate carrier parents heterozygous and unaffected, and in compound‑heterozygous families the two variants co‑segregate in trans with the phenotype PMID:23541340, PMID:27087618, PMID:39847269, PMID:40410890. Collectively, these reports encompass several dozen affected individuals, with the Chinese series alone summarizing 33 patients and demonstrating statistically significant genotype–phenotype correlations (higher neurological complication rates in truncating or missense‑plus‑truncating genotypes versus biallelic missense; p = 0.001) PMID:40410890.
The variant spectrum includes canonical splice‑site, frameshift, and missense changes dispersed across the protease domain and regions implicated in CLPX docking. Reported pathogenic or likely pathogenic CLPP variants in Perrault syndrome include:
Phenotypically, CLPP‑related Perrault syndrome consistently involves bilateral sensorineural hearing loss (HP:0000407 / HP:0008619), primary or secondary ovarian insufficiency (HP:0008209, HP:0000869, HP:0000133), and variable neurologic abnormalities, including seizures (HP:0001250), intellectual disability (HP:0001249), global developmental delay (HP:0001263), spasticity and muscle weakness (HP:0001324), peripheral neuropathy (HP:0009830), and brain atrophy PMID:25956234, PMID:27087618, PMID:39847269, PMID:34338890, PMID:40410890. Disease severity ranges from milder cases without overt neurologic signs PMID:27087618 to severe early‑onset neurodegenerative presentations with regression PMID:25956234. Geographic representation includes Middle Eastern (Saudi, Turkish, Iranian), European, Han Chinese, and South Asian families, suggesting no strict ethnic restriction but potential population‑specific alleles.
CLPP encodes the mitochondrial ClpP protease, a central component of the mitochondrial protein quality‑control machinery that partners with the AAA+ unfoldase CLPX (forming the ClpXP complex). The original disease gene study emphasized CLPP’s role in mitochondrial proteostasis, noting that Perrault‑associated variants cluster in conserved regions important for the barrel chamber that binds unfolded proteins, and that the phenotype aligns with mitochondrial dysfunction PMID:23541340. Detailed biochemical work on Perrault‑linked alleles has since clarified the mechanistic impact. A functional study of CLPP mutants showed that c.685T>G (p.Tyr229Asp), a variant adjacent to the active site, abolishes peptidase activity and prevents CLPX docking, effectively blocking protein and peptide substrate turnover; in contrast, the hydrophobic‑pocket variants p.Thr145Pro and p.Cys147Ser, which lie near the CLPX docking site, produce a range of defects from near‑normal to severely perturbed oligomerization and “gain‑of‑function” enhanced peptidase activity, indicating that both loss‑of‑function and dysregulated protease activity can underlie disease PMID:30150665.
Additional functional evidence supports a broader role of CLPP in mitochondrial and cellular stress pathways. In human cells, CLPP participates in degradation of abnormal mitochondrial proteins; recent work shows that CLPP (with CLPX) targets mutant mitochondrial tRNA 2‑thiouridylase MTU1 for proteolysis, and CLPP knockdown stabilizes mutant MTU1 and restores mt‑tRNA thiolation, linking CLPP activity directly to regulation of mitochondrial translation components PMID:38113276. Although not performed in Perrault patient tissue, these data reinforce the concept that altered CLPP activity disrupts mitochondrial proteostasis and protein synthesis, a plausible mechanism for the neurosensory and gonadal phenotypes. The Han Chinese Perrault study further provided experimental confirmation that the splice‑site variant c.270+?C causes aberrant splicing, with intron retention and altered exon usage demonstrated by minigene assays, thereby establishing a clear loss‑of‑function effect PMID:40410890.
Taken together, human genetic findings and functional assays converge on loss of normal CLPP function and/or toxic gain‑of‑function of the protease as the principal pathogenic mechanisms. This manifests within mitochondria as impaired protein quality control, altered turnover of mitochondrial enzymes, and likely disruption of mitochondrial translation, especially in tissues with high energy and proteostasis demands such as cochlea, central nervous system, and gonads PMID:23541340, PMID:30150665, PMID:38113276.
Some CLPP variants are not clearly disease‑causing. In a Yemeni family with primary ovarian insufficiency and azoospermia due to a homozygous PSMC3IP stop‑gain mutation, an accompanying homozygous CLPP missense variant c.100C>T (p.Pro34Ser) showed mitochondrial fragmentation in vitro but no substantial defects in mitochondrial targeting or respiration; the authors concluded that this CLPP variant likely does not contribute significantly to ovarian insufficiency in that family PMID:29240891. Additionally, a Pakistani hearing‑loss cohort identified a novel CLPP variant c.257G>A (p.Cys86Tyr) associated with prelingual deafness, but it was considered a variant of uncertain significance under ACMG criteria, reflecting the need for caution when attributing isolated hearing loss to CLPP without full Perrault features or segregation/functional data PMID:32842620. These observations do not weaken the core Perrault association but highlight that not all rare CLPP missense variants are pathogenic and underscore the importance of biallelic, clearly damaging alleles plus compatible phenotypes.
The weight of evidence from multiple independent families, robust segregation, variant spectrum and recurrence, and well‑characterised functional consequences provides a Definitive gene–disease relationship between biallelic CLPP variants and Perrault syndrome type 3. The disorder is fully penetrant for sensorineural hearing loss, with high but not complete penetrance for ovarian insufficiency in females and variable neurologic involvement. Pathogenic variants include both missense and truncating alleles, often in the proteolytic core or CLPX‑interaction regions, and genotype–phenotype correlations suggest that genotypes with at least one truncating variant confer higher risk of neurologic complications PMID:40410890. Current evidence likely reaches or exceeds typical ClinGen scoring caps for both genetic and experimental data.
For clinical diagnostics, comprehensive sequencing of CLPP (including copy‑number assessment and splice‑site interrogation) is recommended in individuals with bilateral sensorineural hearing loss and ovarian insufficiency, particularly when accompanied by neurologic signs. Variant interpretation should prioritize clearly damaging biallelic variants with segregation support and, where available, functional confirmation of loss‑of‑function or dysregulated protease activity.
Key take‑home sentence: Biallelic, typically loss‑of‑function or function‑altering variants in CLPP cause autosomal recessive Perrault syndrome type 3 with consistent sensorineural hearing loss and frequent ovarian insufficiency and neurologic involvement, establishing CLPP as a definitive diagnostic and counselling target in this syndrome.
Gene–Disease AssociationDefinitiveMultiple unrelated families with biallelic CLPP variants and classic Perrault features, strong segregation across consanguineous and compound-heterozygous pedigrees, and concordant functional evidence from protease and splicing assays accumulated over >10 years. Genetic EvidenceStrongAt least 8 independent CLPP-Perrault families plus additional cohort cases (≈30+ patients overall), with homozygous or compound-heterozygous missense, splice, and truncating variants segregating with autosomal recessive Perrault syndrome in multiple populations; genotype–phenotype correlations and biallelic LoF/damaging alleles are consistent across studies. Functional EvidenceStrongBiochemical studies show Perrault-associated variants disrupt CLPP peptidase activity, CLPX docking, oligomerization, or splicing, and broader work confirms CLPP’s central role in mitochondrial proteostasis and regulation of mitochondrial translation components, providing a coherent pathogenic mechanism that matches the neurosensory and gonadal phenotypes. |