PEX3 and Peroxisome Biogenesis Disorder

PEX3 mutations underlie a spectrum of peroxisome biogenesis disorders that fall within the Zellweger syndrome continuum. The association is supported by multiple case reports and multi‐patient studies, which collectively document autosomal recessive inheritance and a range of clinical presentations from severe neonatal lethality to less severe, later‑onset phenotypes (PMID:10968777).

Several independent reports have detailed patients with classic features of Zellweger syndrome as well as milder forms such as infantile Refsum disease. Notably, cases have revealed typical peroxisomal dysfunction through biochemical analyses and morphological assessments, thereby strengthening the clinical validity of PEX3 as a causal gene in peroxisome biogenesis defects (PMID:20033294).

Family-based segregation studies further reinforce the association; affected relatives in multiple pedigrees carry pathogenic variants in PEX3, confirming an autosomal recessive mode of transmission. A variety of mutation types, including splice site defects, frameshift mutations, and nonsense mutations, have been detected. For example, the variant c.413G>A (p.Gly138Glu) has been reported in affected individuals and is predicted to cause loss of normal protein function (PMID:10848631).

Genetic evidence is bolstered by the identification of a diverse variant spectrum across unrelated probands. Studies have described missense, nonsense, and frameshift variants within PEX3 that consistently result in defective peroxisome assembly. This convergence of data from independent case reports and case series provides strong support for the gene–disease association (PMID:27557811).

Functional assessments using cellular and animal models have demonstrated that mutant forms of PEX3 fail to restore peroxisome biogenesis. In vitro studies in Chinese hamster ovary cells and other systems show that PEX3 with pathogenic alterations is unable to support peroxisomal membrane protein import and de novo peroxisome formation, thus providing mechanistic insight into the resultant cellular phenotype (PMID:18543353; PMID:22624858).

In summary, the integration of robust genetic data with compelling functional studies clearly establishes a strong association between PEX3 mutations and peroxisome biogenesis disorder. Despite the clinical heterogeneity observed among affected individuals, the consistent loss-of-function effects of PEX3 variants support their pathogenicity and underscore the importance of screening for these mutations in patients with suspected peroxisomal defects.

Key take‑home sentence: Comprehensive molecular testing for PEX3 variants is essential for accurate diagnosis and clinical management of peroxisome biogenesis disorders.

References

• American journal of human genetics • 2000 • Pex3 is the causal gene responsible for peroxisome membrane assembly-defective Zellweger syndrome of complementation group G PMID:10968777
• Journal of inherited metabolic disease • 2009 • Zellweger syndrome with unusual findings: non-immune hydrops fetalis, dermal erythropoiesis and hypoplastic toe nails PMID:20033294
• Brain & development • 2013 • Newly identified milder phenotype of peroxisome biogenesis disorder caused by mutated PEX3 gene PMID:23245813
• JIMD reports • 2017 • Novel PEX3 Gene Mutations Resulting in a Moderate Zellweger Spectrum Disorder PMID:27557811
• Molecular biology of the cell • 2000 • The peroxin pex3p initiates membrane assembly in peroxisome biogenesis PMID:10848631
• Cell biochemistry and function • 2008 • Isolation and characterization of novel phenotype CHO cell mutants defective in peroxisome assembly PMID:18543353

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