PEX2 – Zellweger spectrum disorders

PEX2 encodes a peroxisomal membrane RING finger protein essential for peroxisome biogenesis. Biallelic PEX2 mutations underlie Zellweger spectrum disorders (ZSDs), an autosomal recessive (AR) peroxisome biogenesis disorder characterized by defective protein import and impaired very long chain fatty acid β-oxidation. Multiple independent studies over >15 years have confirmed this gene–disease relationship with consistent segregation and complementary functional data.

Genetic evidence supports a definitive AR association. Six unrelated probands (1 infantile Refsum disease IRD patient PMID:10528859, 1 adult-onset mild ZSD case PMID:23430938, and 4 CG10 patients PMID:14630978) harbor compound heterozygous or homozygous PEX2 variants. Eleven distinct variants include nine predicted loss-of-function alleles (nonsense and frameshift) and two missense changes, consistent with a loss-of-function mechanism. Reported segregation is concordant with AR inheritance and no conflicting co-segregation has been described.

Phenotypic spectrum spans severe neonatal ZSD with hypotonia, feeding difficulties and early death to milder childhood or adult-onset ataxia and neuropathy. Classic features include hypotonia, hepatic dysfunction and sensorineural hearing impairment, whereas hypomorphic alleles (e.g., p.Glu55Lys) lead to infantile Refsum-like phenotypes and late-onset cerebellar ataxia with preserved cognition.

Multiple cell‐based complementation assays demonstrate that wild-type PEX2 cDNA restores peroxisome assembly and matrix protein import in PEX2-deficient CHO cells (PMID:10528859). Variants predicted to truncate the RING finger domain abolish peroxisomal protein import and β-oxidation of very long chain fatty acids.

Temperature‐sensitivity studies show that the p.Glu55Lys missense allele confers mosaic peroxisome assembly at 30 °C but not 37 °C, explaining the milder IRD phenotype and demonstrating allelic heterogeneity in PEX2-related PBDs (PMID:11330043).

A Pex2 knockout mouse recapitulates human pathology, including delayed cortical neuronal migration, Purkinje cell loss, cerebellar hypoplasia and tissue accumulation of very long chain fatty acids and plasmalogen deficiency, confirming pathogenicity in vivo (PMID:11478384).

Integrating genetic, cellular and animal model data establishes a definitive PEX2–ZSD association. Clinical testing for PEX2 variants is recommended in AR peroxisome biogenesis disorders across the severity spectrum.

References

• 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
• Cell biochemistry and biophysics • 2000 • Temperature sensitivity in peroxisome assembly processes characterizes milder forms of peroxisome biogenesis disorders. PMID:11330043
• JIMD reports • 2012 • Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations. PMID:23430938
• Pediatric research • 2004 • Novel mutations in the PEX2 gene of four unrelated patients with a peroxisome biogenesis disorder. PMID:14630978
• Journal of molecular neuroscience : MN • 2001 • The peroxisome deficient PEX2 Zellweger mouse: pathologic and biochemical correlates of lipid dysfunction. PMID:11478384

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