PMPCA – Mitochondrial Disease

PMPCA encodes the α-subunit of the mitochondrial processing peptidase (α-MPP), which cleaves targeting presequences from nuclear-encoded proteins imported into mitochondria. Biallelic pathogenic variants in PMPCA have been linked to a severe, early-onset mitochondrial disease presenting with developmental delay, hypotonia, respiratory insufficiency, lactic acidosis and blindness.

In a large Lebanese family, whole-exome sequencing of a female proband and her unaffected parents revealed two compound heterozygous PMPCA variants that were also present in her affected male cousin, segregating with disease in trans (1 additional affected relative). These findings established autosomal recessive inheritance for PMPCA-related mitochondrial disease (PMID:27148589).

The identified variants include c.1130C>T (p.Ala377Val) and c.1066G>A (p.Gly356Ser), both clustering within the glycine-rich loop critical for substrate binding. A third variant, c.1129G>A (p.Ala377Thr), was also reported in another affected family member, illustrating a missense-only variant spectrum with no recurrent founder alleles.

Functional studies on patient fibroblasts demonstrated markedly reduced α-MPP levels by western blot and misprocessing of frataxin precursor by immunofluorescence, consistent with impaired mitochondrial protein maturation. Rescue experiments with exogenous wild-type PMPCA cDNA restored enzyme levels and frataxin processing, confirming loss-of-function as the underlying mechanism (PMID:27148589).

No studies to date have reported conflicting genotype–phenotype data for this association. The combination of segregation in affected relatives and robust functional rescue strongly supports a causal role for PMPCA variants in autosomal recessive mitochondrial disease.

Key Take-home: Biallelic PMPCA missense variants impair α-MPP function, leading to defective mitochondrial protein maturation and a severe multisystem mitochondrial disease, underscoring the clinical utility of PMPCA sequencing in undiagnosed pediatric mitochondrial disorders.

References

• Cold Spring Harbor Molecular Case Studies • 2016 • Mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-α protein (PMPCA) cause a severe mitochondrial disease PMID:27148589

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