PEX12 – Peroxisome Biogenesis Disorder

This summary reviews the association between PEX12 and peroxisome biogenesis disorder, emphasizing robust genetic and functional evidence that underpins the clinical diagnosis. Multiple independent studies have established that loss‐of‐function mutations in PEX12 lead to peroxisome assembly defects, resulting in a spectrum of clinical features including ataxia, dysarthria, dry skin, areflexia, and hypotonia (PMID:15184617). The body of evidence includes case reports, family segregation analyses, and multi‐patient cohort studies that consistently reveal autosomal recessive transmission. These studies have identified numerous variants in PEX12 demonstrating concordance between genotype and the observed biochemical abnormalities in patient fibroblasts. The extent of the evidence supports its utility for diagnostic decision‑making, clinical interpretation, and potential commercial applications.

Genetic evidence indicates an autosomal recessive mode of inheritance, with multiple families demonstrating clear segregation of pathogenic variants. Detailed mutational analyses across independent cohorts have disclosed several loss‑of‑function alleles, including the representative variant c.949C>T (p.Leu317Phe) (PMID:26094004). Segregation studies documented an excess of affected relatives, with reports noting at least 19 additional affected individuals in extended families. This genetic burden, along with consistent reports from independent studies, substantiates a strong genetic link between PEX12 mutations and the clinical disorder. The variant spectrum predominantly comprises frameshift, nonsense, and splice‐site alterations that abolish function of the PEX12 protein.

Functional studies provide complementary support, with experiments demonstrating that mutations in PEX12 disrupt peroxisomal matrix protein import. Complementation assays in patient‑derived cells and CHO cell models have shown that introduction of wild‑type PEX12 restores peroxisome biogenesis (PMID:9792857). Cellular and biochemical assessments reveal that loss of PEX12 function underlies the defective metabolic processing characteristic of the disorder. Additionally, rescue experiments and protein localization studies support the role of the PEX12 RING finger domain in mediating critical protein‑protein interactions necessary for peroxisomal assembly (PMID:9632816). These functional data provide moderate but highly relevant experimental evidence that bolsters the genetic findings.

The mechanistic insights indicate that PEX12 mutations lead to a failure in peroxisomal protein import, which is central to the pathogenesis of peroxisome biogenesis disorder. The loss of the zinc‑binding RING domain impairs interactions with other peroxins, including PEX5 and PEX10, thereby disrupting the entire import process (PMID:10562279). Translational or internal initiation events, observed in some mutant alleles, may modulate the severity of the phenotype, creating variability in clinical presentation. Such insights help explain the spectrum of clinical features observed among patients. Overall, the experimental observations align well with the genetic data, creating a coherent narrative linking genotype to phenotype.

Although early reports had considered distinct metabolic defects, subsequent analyses refuted the concept of trihydroxycholestanoyl‑CoA oxidase deficiency as an isolated entity (PMID:15184617). Instead, the convergence of biochemical, genetic, and functional evidence firmly attributes the clinical presentation to peroxisome biogenesis defects arising from PEX12 mutations. This re‐evaluation highlights the need for comprehensive genetic testing in patients with atypical biochemical profiles. Conflicting evidence from earlier diagnostic approaches has been resolved by the integration of molecular data, thereby refining the diagnostic criteria for the disorder.

In summary, the aggregated evidence from case reports, family studies, and functional assays supports a strong gene‑disease association for PEX12 with peroxisome biogenesis disorder. The variety of loss‑of‑function mutations, robust segregation data, and consistent experimental findings collectively endorse the validity of this association for diagnostic and clinical applications. Additional evidence beyond the ClinGen scoring maximum further reinforces this assertion.

Key Take‑home sentence: PEX12 is conclusively implicated in peroxisome biogenesis disorder, making it a critical marker for diagnosis, genetic counseling, and tailored therapeutic strategies.

References

• Neurology • 2004 • Reinvestigation of trihydroxycholestanoic acidemia reveals a peroxisome biogenesis disorder PMID:15184617
• Molecular Biology Reports • 2015 • A novel mutation in the PEX12 gene causing a peroxisomal biogenesis disorder PMID:26094004
• Nature Genetics • 1997 • Isolation of the human PEX12 gene, mutated in group 3 of the peroxisome biogenesis disorders PMID:9090384
• Neuropediatrics • 2016 • Effect of l-Arginine in One Patient with Peroxisome Biogenesis Disorder due to PEX12 Deficiency PMID:26947510
• American Journal of Human Genetics • 1998 • Phenotype-genotype relationships in complementation group 3 of the peroxisome-biogenesis disorders PMID:9792857
• 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
• 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

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