CLPP and Perrault Syndrome

Recent studies have established a strong association between mutations in CLPP and Perrault syndrome, a rare autosomal recessive disorder. Multiple case reports have identified pathogenic variants in CLPP across diverse populations, with clear evidence of segregation in consanguineous families and novel variant discovery by exome sequencing (PMID:25956234, PMID:27087618).

Genetic evidence consistently supports the role of CLPP in disease etiology. In particular, several studies have reported missense mutations, including the allele c.624C>G (p.Ile208Met), along with other loss‑of‑function variants that segregate with the Perrault syndrome phenotype. These findings were supported by robust segregation analyses, where affected relatives within multiple families further confirmed the autosomal recessive pattern (PMID:27087618).

Functional assessments have demonstrated that mutant CLPP impairs mitochondrial protease activity, which is essential for maintaining mitochondrial protein homeostasis. Experimental studies using cellular and animal models have revealed that disruptions in CLPP function lead to mitochondrial dysfunction, thereby recapitulating key aspects of the clinical presentation seen in Perrault syndrome patients (PMID:11790733, PMID:30150665).

The constellation of symptoms reported in affected individuals—including muscle weakness, intellectual disability, sensorineural hearing impairment, secondary amenorrhea, and gonadal dysgenesis—further supports the clinical validity of the association. This phenotypic spectrum emphasizes that CLPP mutations not only disrupt mitochondrial function but also result in a multisystem disorder, aligning with the broad clinical criteria for Perrault syndrome (PMID:23541340).

Moreover, the high degree of experimental concordance, from in vitro functional assays to animal model validations, underpins the pathogenic mechanism as being driven by loss of proteolytic activity. Such findings are crucial for diagnostic decision‑making and pave the way for potential therapeutic endeavors, as targeting mitochondrial dysfunction may offer a route for clinical intervention.

In summary, the integration of rigorous genetic and functional evidence has solidified the link between CLPP and Perrault syndrome, underlining its clinical utility as a diagnostic marker. Key take‑home message: Genetic testing for CLPP mutations should be strongly considered in patients with features of Perrault syndrome to enable timely and appropriate management.

References

• Journal of Neurological Sciences • 2015 • 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 PMID:25956234
• Journal of Clinical Research in Pediatric Endocrinology • 2016 • A Novel Missense Mutation in the CLPP Gene Causing Perrault Syndrome Type 3 in a Turkish Family PMID:27087618
• American Journal of Human Genetics • 2013 • Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP‑dependent chambered protease PMID:23541340
• Journal of Bacteriology • 2002 • The ClpXP ATP‑dependent protease regulates flagellum synthesis in Salmonella enterica serovar typhimurium PMID:11790733
• Scientific Reports • 2018 • Perrault syndrome type 3 caused by diverse molecular defects in CLPP PMID:30150665

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