PEX10 – Zellweger spectrum disorders

PEX10 encodes a peroxisomal membrane RING finger protein essential for peroxisomal matrix protein import. Biallelic loss-of-function or missense variants in PEX10 underlie Zellweger spectrum disorders (ZSDs), a spectrum of autosomal recessive peroxisome biogenesis disorders characterized by neurodevelopmental impairment, hepatic dysfunction, and dysmorphic features.

Initial identification of PEX10 defects in complementation group 7 was reported in two unrelated ZSD patients, including a homozygous splice donor mutation leading to exon skipping and a compound heterozygote for a missense variant in the zinc-binding domain and a nonsense allele (PMID:9683594). Subsequent analysis of four severe Zellweger syndrome and one neonatal adrenoleukodystrophy patient revealed nonsense, frameshift, and splice-site mutations removing large portions of PEX10, as well as a partially functional H290Q allele in a milder case (PMID:10862081). A cohort of 11 Japanese ZS patients all harbored a homozygous founder 2-bp deletion (c.795_796del (p.Arg265fs)) demonstrating a population-specific recurrent LoF variant (PMID:12794690).

A broad variant spectrum includes at least 18 unique LoF alleles (nonsense, frameshift, canonical splice) and multiple missense changes clustering in the C-terminal RING domain. Novel and recurrent missense variants such as c.827G>T (p.Cys276Phe) have been linked to milder, ataxic phenotypes in multigenerational kindreds (PMID:27230853). Single cases with maternal uniparental isodisomy confirmed frameshift alleles in recessive ZSD (PMID:17702006).

Familial segregation is supported by at least 7 additional affected relatives across four pedigrees: two sibs in the Japanese founder study, three affected siblings in a French ataxia family, and two further affected in ataxic and PBD6B kindreds. The autosomal recessive inheritance, extensive segregation, and recessive in trans mutations confirm pathogenicity.

Functional complementation assays in patient fibroblasts and CHO mutant cells demonstrated that PEX10 deficiency abolishes peroxisomal matrix protein import, while overexpression of PEX10 (or PEX5) rescues import defects. Yeast two-hybrid and coimmunoprecipitation studies showed that PEX10 interacts directly with PEX5 and PEX12 downstream of receptor docking, establishing a loss-of-function mechanism (PMID:10562279; PMID:10837480).

Integration of genetic and functional data across >20 unrelated probands, 18 distinct pathogenic alleles, and concordant experimental evidence supports a Strong gene–disease relationship according to ClinGen. Comprehensive PEX10 sequencing should be included in diagnostic gene panels for patients with suspected ZSD, enabling early molecular diagnosis and family counseling.

References

• American journal of human genetics • 1998 • Identification of PEX10, the gene defective in complementation group 7 of the peroxisome-biogenesis disorders. PMID:9683594
• Human mutation • 2000 • Phenotype-genotype relationships in PEX10-deficient peroxisome biogenesis disorder patients. PMID:10862081
• 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
• Journal of neurology • 2016 • Expanding the spectrum of PEX10-related peroxisomal biogenesis disorders: slowly progressive recessive ataxia. PMID:27230853
• Journal of inherited metabolic disease • 2009 • A PEX10 defect in a patient with no detectable defect in peroxisome assembly or metabolism in cultured fibroblasts. PMID:19127411
• American journal of medical genetics. Part A • 2007 • Zellweger syndrome resulting from maternal isodisomy of chromosome 1. PMID:17702006
• The Journal of cell biology • 1999 • PEX12 interacts with PEX5 and PEX10 and acts downstream of receptor docking in peroxisomal matrix protein import. PMID:10562279
• The Journal of biological chemistry • 2000 • Molecular anatomy of the peroxin Pex12p: ring finger domain is essential for Pex12p function and interacts with the peroxisome-targeting signal type 1-receptor Pex5p and a ring peroxin, Pex10p. PMID:10837480

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