PEX12 – Zellweger Spectrum Disorders

PEX12 is a gene implicated in Zellweger spectrum disorders, a group of autosomal recessive peroxisomal biogenesis disorders characterized by severe multi‐system involvement. Multiple independent studies have reported that loss-of-function mutations in PEX12, including recurrent frameshift alleles, underlie this disorder. In particular, several case reports describe compound heterozygous mutations with one allele often harboring a frameshift deletion such as c.888_889del (p.Leu297fs) (PMID:26094004), confirming the molecular lesion responsible for the phenotype.

Genetic evidence is robust with over 15 unrelated probands reported across independent studies (PMID:15241794), and familial segregation analyses further identify 19 affected relatives carrying pathogenic variants. In these cases, variants typically disrupt the open reading frame, resulting in the loss of the critical C-terminal zinc ring domain required for proper peroxisomal protein import.

Detailed case reports have documented variable mutation spectrums in PEX12. For example, one study identified patients harboring both a novel 2-bp insertion and a recurrent 2-bp deletion with resultant frameshift effects (PMID:26094004). Moreover, patients from multi-patient studies have consistently exhibited autosomal recessive inheritance, with molecular findings that corroborate the clinical heterogeneity observed in Zellweger spectrum disorders (PMID:14571262).

Functional studies further support the pathogenic role of PEX12 mutations by showing that loss-of-function disrupts peroxisomal matrix protein import. Cellular assays and complementation experiments demonstrate that perturbation of the zinc finger domain leads to mislocalization of peroxisomal proteins and recapitulates disease-relevant cellular phenotypes (PMID:9632816; PMID:10562279).

Overall, the convergence of detailed genetic data and experimental evidence confirms a strong gene-disease association for PEX12 in Zellweger spectrum disorders. The clinical manifestations, including liver abnormalities, sensorineural hearing impairment, and retinopathy, are in keeping with the multi-system dysfunction expected from defective peroxisomal biogenesis.

Key Take‑home Sentence: The integration of recurrent loss-of-function mutations, segregation data among affected relatives, and concordant functional assays establishes PEX12 as a critical determinant in the diagnosis of Zellweger spectrum disorders.

References

• Molecular biology reports • 2015 • A novel mutation in the PEX12 gene causing a peroxisomal biogenesis disorder PMID:26094004
• European journal of pediatrics • 2015 • Zellweger syndrome and secondary mitochondrial myopathy PMID:25287621
• The Journal of cell biology • 1999 • PEX12 interacts with PEX5 and PEX10 and acts downstream of receptor docking in peroxisomal matrix protein import PMID:10562279
• Human mutation • 2004 • Identification of the molecular defect in patients with peroxisomal mosaicism using a novel method involving culturing of cells at 40 degrees C: implications for other inborn errors of metabolism PMID:15241794
• Molecular and cellular biology • 1998 • PEX12, the pathogenic gene of group III Zellweger syndrome: cDNA cloning by functional complementation on a CHO cell mutant, patient analysis, and characterization of PEX12p PMID:9632816

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