PEX26 and Peroxisome Biogenesis Disorder

The association between PEX26 and peroxisome biogenesis disorder is supported by a broad base of evidence from case reports, multi‐patient studies, and functional assays. Studies have shown that biallelic mutations in PEX26, following an autosomal recessive inheritance pattern, lead to a disruption in peroxisome formation and function, manifesting clinically as severe multi‐system involvement. In affected individuals, presentations include visual and hearing impairment, hepatosplenomegaly, and global developmental delay (PMID:39359950).

Genetic evidence is robust with multiple types of deleterious variants identified, including frameshift, nonsense, and splice site mutations. For instance, the reported variant c.214G>T (p.Glu72Ter) illustrates the clear impact on protein function and has been observed in independent families. Segregation analyses in several studies further corroborated the association, with affected relatives consistently carrying pathogenic alleles (PMID:12851857).

Multi‐patient evaluations have documented over 20 probands harboring diverse PEX26 mutations that disrupt peroxisomal biogenesis. These studies not only highlight the mutation spectrum but also provide genotype–phenotype correlations that help define the boundaries between Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease phenotypes (PMID:12851857).

Functional investigations lend further support to the role of PEX26 in peroxisome formation. Cellular assays demonstrate that loss‐of‐function mutations impair peroxisomal import of matrix proteins, and rescue experiments in deficient cell models restore normal peroxisome assembly. Such experiments have been essential in validating the pathogenicity of the observed variants (PMID:15858711, PMID:30366024).

Some reports have noted atypical clinical courses or overlapping features with other peroxisomal disorders, thereby expanding the known phenotypic spectrum. However, the preponderance of consistent genetic and experimental data solidifies the gene–disease relationship, despite these outliers.

Overall, the convergence of molecular, clinical, and functional data provides compelling support for a strong association between PEX26 mutations and peroxisome biogenesis disorder. This integrated evidence base offers clear utility in diagnostic decision‑making and underscores the clinical relevance of testing for PEX26 variants.

Key Take‑home Sentence: Comprehensive genetic and functional data affirm that pathogenic variants in PEX26 are a strong indicator of peroxisome biogenesis disorder, making it a critical target in molecular diagnostics.

References

• Clinica chimica acta; international journal of clinical chemistry • 2013 • Analysis of a Chinese pedigree with Zellweger syndrome reveals a novel PEX1 mutation PMID:23247051
• Molecular syndromology • 2024 • Biallelic Deletion of PEX26 Exon 4 in a Boy with Phenotypic Features of both Zellweger Syndrome and Infantile Refsum Disease PMID:39359950
• American journal of human genetics • 2003 • Mutations in novel peroxin gene PEX26 that cause peroxisome‑biogenesis disorders of complementation group 8 provide a genotype‑phenotype correlation PMID:12851857
• 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

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