PEX6 – Zellweger spectrum disorders

Peroxisome biogenesis disorders (PBDs) comprise a spectrum of autosomal recessive conditions characterized by defective peroxisome assembly. Biallelic mutations in PEX6 account for the complementation group C Zellweger phenotype and are responsible for approximately 80% of PBD cases in this group ([PMID:9671729]). Clinical diagnosis relies on elevated very‐long‐chain fatty acids and characteristic brain MRI findings, with genetic confirmation by sequencing of PEX6.

Genetic evidence includes a cohort of 75 unrelated probands harboring pathogenic PEX6 variants identified by high‐resolution melting analysis and sequencing ([PMID:19877282]). A French‐Canadian founder deletion c.802_815del (p.Asp268fs) was observed in five patients, yielding a regional incidence of 1 in 12,191 live births and a carrier frequency of 1 in 55 ([PMID:22894767]). Case reports have expanded the spectrum to include hypomorphic and deep‐intronic alleles: for instance, compound heterozygosity for c.315G>A (p.Trp105Ter) and c.2095-3>G with demonstrated exon skipping by minigene assay in a Chinese neonate ([PMID:39013483]), and a mild p.Ala94Pro homozygote presenting with adrenal insufficiency at age 2 ([PMID:29047053]).

The variant spectrum encompasses over 100 alleles across 17 exons, including nonsense, frameshift, canonical splice‐site, missense, and intronic changes leading to nonsense‐mediated decay. Recurrent alleles include the p.Arg860Trp substitution subject to allelic expression imbalance, where overrepresentation of the mutant transcript causes a dominant‐acting biogenesis defect in seven unrelated individuals ([PMID:29220678]). Segregation of pathogenic variants has been confirmed in multiple sibships and consanguineous families.

Functional studies demonstrate that PEX6 encodes a AAA ATPase that heterodimerizes with PEX1 to drive peroxisomal matrix protein import. Yeast two‐hybrid and in vitro assays confirm PEX1–PEX6 complex formation, with allele‐specific suppression of PEX6‐deficient phenotypes by overexpression of PEX1 and vice versa ([PMID:9671729]). Patient fibroblasts and PEX6 knockout cells exhibit impaired PTS1‐ and PTS2‐mediated import, which is rescued by ectopic wild‐type PEX6 expression ([PMID:36249295]).

The mechanism of pathogenicity is loss of function with defective dislocation of peroxisomal matrix proteins, leading to multi‐organ dysfunction. Minigene assays for splice variants (e.g., c.2095-3>G) show exon 11 skipping and predicted nonsense‐mediated decay, highlighting the need to assess noncoding regions in diagnostic sequencing ([PMID:39013483]).

Integration of genetic and functional data supports a Strong clinical validity classification. PEX6 sequencing should be included in neonatal screening panels for PBDs, with functional assays guiding interpretation of novel splice and hypomorphic alleles. Key Take-home: PEX6 loss‐of‐function variants underlie autosomal recessive Zellweger spectrum disorders, with robust genetic and experimental evidence guiding accurate diagnosis and potential future gene therapy approaches.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1998 • Disruption of a PEX1-PEX6 interaction is the most common cause of the neurologic disorders Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease. PMID:9671729
• Human mutation • 2010 • Spectrum of PEX6 mutations in Zellweger syndrome spectrum patients. PMID:19877282
• BMC medical genetics • 2012 • A founder mutation in the PEX6 gene is responsible for increased incidence of Zellweger syndrome in a French Canadian population. PMID:22894767
• Gene • 2024 • A novel splice variant in intron 10 of PEX6 is associated with Zellweger Syndrome in a Chinese neonate. PMID:39013483
• Ophthalmology science • 2021 • PEX6 Mutations in Peroxisomal Biogenesis Disorders: An Usher Syndrome Mimic. PMID:36249295
• American journal of human genetics • 2017 • Allelic Expression Imbalance Promoting a Mutant PEX6 Allele Causes Zellweger Spectrum Disorder. PMID:29220678

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