PEX6 – Peroxisome Biogenesis Disorder

PEX6 encodes a peroxisomal AAA ATPase essential for matrix protein import in autosomal recessive (AR) peroxisome biogenesis disorders (PBD), including the Zellweger spectrum. Loss of PEX6 function disrupts peroxisome assembly, leading to multisystem disease with neonatal hypotonia, seizures, adrenal insufficiency, sensorineural hearing loss and retinal dystrophy. Genetic testing of PEX6 is therefore critical in PBD diagnosis and management.

Multiple cohort and case series have identified PEX6 mutations in over 75 unrelated probands across diverse ethnicities. A genomic structure study in 10 patients (18 alleles) first defined PEX6 mutation spectra (PMID:10408779). High-throughput sequencing in 75 complementation group C patients revealed 77 distinct PEX6 variants (PMID:19877282). Targeted analysis in 58 PBD-ZSS cases found 71 unique alleles, including 18 novel mutations (PMID:19105186). Additional reports describe novel compound heterozygotes and homozygotes in Chinese and European patients (PMID:31555682; PMID:29047053).

Inheritance is AR with segregation confirmed in at least 2 sib pairs (PMID:12794690). The variant spectrum includes truncating alleles (nonsense, frameshift, splice-site) and missense changes distributed over all 17 exons. Founder and recurrent alleles such as c.1802G>A (p.Arg601Gln) underlie milder Heimler syndrome phenotypes in multiple families (PMID:27302843).

Functional studies elucidate a haploinsufficiency mechanism mediated by disrupted PEX1–PEX6 interactions. Yeast two-hybrid and allele-specific suppression assays demonstrated complex formation is required for peroxisome biogenesis, with mutant alleles showing defective binding rescued by overexpression (PMID:9671729). Structural mapping of missense variants onto a Pex1/Pex6 homology model correlates lesion positions with ATPase domain impairment (PMID:31374812). Patient fibroblast studies confirm impaired PTS1/PTS2 import, reversible by PEX6 overexpression (PMID:36249295).

Conflicting data include in silico predictions suggesting benign effect of c.280G>C (p.Ala94Pro) in a mild Zellweger case (PMID:29047053) and normal very long-chain fatty acids despite pathogenic splice variants such as c.2095-3>G causing exon skipping (PMID:39013483). These underscore phenotype variability and the need for functional assays.

Integrating genetic and functional evidence, PEX6 meets ClinGen Strong gene-disease validity criteria. AR PEX6 variants yield PBD with consistent biochemical signatures; functional rescue studies provide mechanistic confirmation. Key take-home: Inclusion of PEX6 in diagnostic panels enables accurate PBD diagnosis and lays groundwork for variant-specific therapeutic strategies.

References

• Human Mutation • 1999 • Genomic structure and identification of 11 novel mutations of the PEX6 (peroxisome assembly factor-2) gene in patients with peroxisome biogenesis disorders. PMID:10408779
• Human Mutation • 2010 • Spectrum of PEX6 mutations in Zellweger syndrome spectrum patients. PMID:19877282
• Human Mutation • 2009 • Identification of novel mutations and sequence variation in the Zellweger syndrome spectrum of peroxisome biogenesis disorders. PMID:19105186
• Annals of Translational Medicine • 2019 • Two novel mutations of PEX6 in one Chinese Zellweger spectrum disorder and their clinical characteristics. PMID:31555682
• Journal of Applied Genetics • 2017 • Mild Zellweger syndrome due to a novel PEX6 mutation: correlation between clinical phenotype and in silico prediction of variant pathogenicity. PMID:29047053
• American Journal of Medical Genetics Part A • 2003 • Genetic heterogeneity of peroxisome biogenesis disorders among Japanese patients: evidence for a founder haplotype for the most common PEX10 gene mutation. PMID:12794690
• PNAS • 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
• Int J Mol Sci • 2019 • Structural Mapping of Missense Mutations in the Pex1/Pex6 Complex. PMID:31374812
• Ophthalmology Science • 2021 • PEX6 Mutations in Peroxisomal Biogenesis Disorders: An Usher Syndrome Mimic. PMID:36249295
• Gene • 2024 • A novel splice variant in intron 10 of PEX6 is associated with Zellweger Syndrome in a Chinese neonate. PMID:39013483
• Eur J Hum Genet • 2016 • Spectrum of PEX1 and PEX6 variants in Heimler syndrome. PMID:27302843

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