PEX26 – Zellweger Spectrum Disorders

Peroxisome biogenesis disorders of the Zellweger spectrum (ZSDs) are autosomal recessive conditions characterized by hepatic dysfunction, hypotonia, craniofacial dysmorphism, sensory deficits, and developmental delay. The PEX26 gene encodes an integral peroxisomal membrane protein that docks the PEX1–PEX6 ATPase complex to peroxisomes, facilitating matrix protein import. Loss of PEX26 function (complementation group 8) disrupts peroxisomal β-oxidation of very long-chain fatty acids (VLCFAs) and other metabolic pathways, driving the multi-system phenotype of ZSDs (PMID:38323187).

Genetic evidence includes five unrelated probands harboring PEX26 variants: a single‐infant case with compound heterozygous c.347T>C (p.Leu116Pro) and c.616C>T (p.Gln206Ter) alleles (PMID:38323187), a Dagestan family with three affected males homozygous for c.347T>A (p.Leu116Gln) (PMID:33912394), and an additional neonate with homozygous c.34del (p.Thr12fs) (PMID:34430430). All variants are predicted loss-of-function or deleterious missense changes segregating in an autosomal recessive manner.

The variant spectrum in ZSD comprises nonsense, frameshift, canonical splice-site, and missense alleles across PEX26. The recurrent c.347A>T/p.Leu116Gln allele was observed at a carrier frequency of <0.000931 in Dagestan, suggesting a population founder effect (PMID:33912394). Most pathogenic changes localize to the N-terminal PEX6-binding domain (aa 29–174), underscoring its critical role in peroxisomal import.

Inheritance is autosomal recessive. Segregation analysis in the Dagestan pedigree demonstrated three affected siblings born to carrier parents, confirming biallelic inheritance (PMID:33912394). No affected heterozygotes have been reported, and obligate carriers are phenotypically normal.

Functional studies demonstrate that PEX26 deficiency abrogates import of both PTS1- and PTS2-targeted matrix proteins, a defect rescued by full-length PEX26 or a splice variant lacking the transmembrane domain (PEX26-Δex5) when mislocalized to mitochondria (PMID:15858711). More recent work reveals that PEX26 homooligomerization and isoform interactions with PEX14 modulate peroxisomal β-oxidation and proliferation, further linking PEX26 structure to function (PMID:30366024).

Taken together, multiple unrelated families, AR segregation, and consistent cellular rescue experiments support a Strong gene–disease association. PEX26 loss-of-function alleles disrupt peroxisome biogenesis via a haploinsufficiency mechanism, with functional complementation assays confirming causality. Clinically, PEX26 sequencing should be included in diagnostic panels for ZSD, enabling early detection and tailored supportive management.

References

• American Journal of Human Genetics • 2005 • Alternative splicing suggests extended function of PEX26 in peroxisome biogenesis. PMID:15858711
• Biochimica et Biophysica Acta. Molecular Cell Research • 2019 • Isoform-specific domain organization determines conformation and function of the peroxisomal biogenesis factor PEX26. PMID:30366024
• Molecular Genetics and Metabolism Reports • 2021 • A novel mutation in the PEX26 gene in a family from Dagestan with members affected by Zellweger spectrum disorder. PMID:33912394
• Translational Pediatrics • 2021 • PEX26 gene genotype-phenotype correlation in neonates with Zellweger syndrome. PMID:34430430
• Translational Pediatrics • 2024 • Identification of a novel heterozygous variant in the PEX26 gene in an infant: a case report. PMID:38323187

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