PEX2 – Peroxisome Biogenesis Disorder

PEX2 encodes a peroxisomal membrane RING-finger protein essential for peroxisome assembly. Biallelic PEX2 variants cause autosomal recessive peroxisome biogenesis disorders (PBDs; MONDO:0019234), including Zellweger syndrome (ZS), neonatal adrenoleukodystrophy, and infantile Refsum disease. Initial functional complementation of PEX2‐deficient fibroblasts by PAF-1 cDNA rescued beta-oxidation and plasmalogen biosynthesis, normalizing peroxisome morphology (PMID:8726233). Subsequent mutation screens identified compound heterozygosity for c.163G>A (p.Glu55Lys) and c.355C>T (p.Arg119Ter) in an infantile Refsum disease patient, demonstrating mosaic peroxisome assembly and residual function at permissive temperature (PMID:11330043).

Genetic evidence confirms autosomal recessive inheritance with at least eight unrelated probands carrying biallelic PEX2 variants: one IRD case with p.Glu55Lys (n = 1) (PMID:10528859), four unrelated PBD patients with truncating alleles including c.314G>A (p.Trp105Ter) (n = 4) (PMID:14630978), and three additional patients with del550C and del642G affecting peroxisome synthesis (n = 3) (PMID:10652207). LoF variants predominate (≥7 truncating alleles) with a single missense hypomorphic allele p.Glu55Lys.

Phenotypic heterogeneity correlates with allelic severity: ZS patients exhibit neonatal hypotonia, feeding difficulties, and skeletal abnormalities; IRD and some neonatal adrenoleukodystrophy cell lines show temperature-sensitive peroxisome assembly. No recurrent or population-specific founder variants have been described for PEX2.

Functional assays in peroxisome-deficient CHO mutants validated pathogenicity: nonsense mutations abolish PTS1/PTS2 import, while p.Glu55Lys retains partial PTS2 import at 30 °C. Complementation of CHO Z65 cells with wild-type PEX2 restored peroxisomal catalase and beta oxidation (PMID:10528859; PMID:11330043).

A PEX2 knockout mouse model recapitulates human disease: homozygous mutants display delayed neuronal migration, cerebellar dysgenesis, accumulation of very long chain fatty acids, and plasmalogen deficiency across tissues (PMID:11478384).

Clinical Validity

Based on eight unrelated probands with biallelic PEX2 variants, multi-family functional complementation, and an animal model, the gene–disease association is classified as Definitive.

Key Take-home

Biallelic PEX2 variants cause autosomal recessive peroxisome biogenesis disorders, and genetic testing coupled with functional assays informs diagnosis, prognosis, and potential rescue strategies.

References

• Pediatric Research • 1996 • Correction by gene expression of biochemical abnormalities in fibroblasts from Zellweger patients. PMID:8726233
• Journal of Medical Genetics • 1999 • Defective PEX gene products correlate with the protein import, biochemical abnormalities, and phenotypic heterogeneity in peroxisome biogenesis disorders. PMID:10528859
• Biochemical and Biophysical Research Communications • 2000 • Molecular mechanism of detectable catalase-containing particles, peroxisomes, in fibroblasts from a PEX2-defective patient. PMID:10652207
• Cell Biochemistry and Biophysics • 2000 • Temperature sensitivity in peroxisome assembly processes characterizes milder forms of peroxisome biogenesis disorders. PMID:11330043
• Journal of Molecular Neuroscience • 2001 • The peroxisome deficient PEX2 Zellweger mouse: pathologic and biochemical correlates of lipid dysfunction. PMID:11478384
• Pediatric Research • 2004 • Novel mutations in the PEX2 gene of four unrelated patients with a peroxisome biogenesis disorder. PMID:14630978

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