PEX3 – Zellweger Spectrum Disorders

PEX3 encodes the peroxisomal membrane protein Pex3p, which is essential for peroxisome membrane assembly and biogenesis. Pathogenic variants in PEX3 cause the autosomal recessive Zellweger spectrum disorders, characterized by impaired peroxisome assembly and accumulation of very long-chain fatty acids.

Clinical Validity

Based on three unrelated probands with biallelic PEX3 variants and concordant functional rescue assays, the gene–disease association is classified as Limited. Genetic data include homozygous splice-site and nonsense variants in patients with classical Zellweger phenotype, without extended segregation data (3 probands) ([PMID:10968777]; [PMID:20033294]).

Genetic Evidence

Inheritance is autosomal recessive. Two key reports describe homozygous PEX3 alleles: an intronic splice acceptor variant c.942-8T>G disrupting exon 11 in a patient cell line (PBDG-02) ([PMID:10968777]), and a nonsense allele c.802A>T (p.Arg268Ter) in a Turkish infant ([PMID:20033294]). No multi-generation segregation studies are available, and no recurrent founder alleles have been reported.

Functional Evidence

Expression of wild-type PEX3 in patient fibroblasts and peroxisome-deficient CHO mutants restored peroxisomal membrane assembly, confirming loss-of-function mechanism ([PMID:10968777]; [PMID:18543353]). Site-directed mutagenesis of conserved PEX3 regions demonstrated impaired PEX19 binding and de novo peroxisome formation when key residues were altered ([PMID:22624858]).

Integration & Conclusion

Although genetic evidence is currently limited to a small number of probands, robust cellular complementation and biochemical studies firmly establish PEX3 as a critical factor for peroxisome biogenesis. Additional case series and segregation analyses would strengthen the association. Key take-home: PEX3 sequencing should be included in diagnostic panels for Zellweger spectrum disorders and informs carrier screening in at-risk families.

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
• Cell biochemistry and function • 2008 • Isolation and characterization of novel phenotype CHO cell mutants defective in peroxisome assembly, using ICR191 as a potent mutagenic agent. PMID:18543353
• Traffic (Copenhagen, Denmark) • 2012 • The role of conserved PEX3 regions in PEX19-binding and peroxisome biogenesis. PMID:22624858

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