PEX10 – Peroxisome Biogenesis Disorder 6B

Autosomal recessive bi-allelic variants in PEX10 cause peroxisome biogenesis disorder 6B, a milder Zellweger spectrum disorder characterized by early‐onset cerebellar dysfunction and multi-system involvement. Multiple unrelated probands presenting with ataxia, tremor, nystagmus, and intellectual disability have been reported over 25 years, with functional assays confirming PEX10’s essential role in peroxisomal matrix protein import.

Genetic Evidence

PEX10‐related PBD6B is inherited in an autosomal recessive manner. At least seven unrelated probands with compound heterozygous or homozygous PEX10 variants have been described (PMID:30640048, PMID:10862081, PMID:40267090). Variant classes include missense (e.g., c.209G>A (p.Gly70Glu)), loss‐of‐function (nonsense and frameshift), and canonical splice variants. A cohort study of Zellweger spectrum disorders identified PEX10 mutations in multiple patients, contributing to a spectrum of PBD‐ZSS genotypes (PMID:19105186).

Segregation analysis in two pedigrees demonstrated that affected sibs co‐segregate compound heterozygous variants, with two additional affected relatives confirmed by molecular testing (PMID:40267090).

Functional Evidence

PEX10 encodes a peroxisomal membrane RING finger protein that interacts directly with PEX5 and PEX12 downstream of receptor docking. Two‐hybrid, coimmunoprecipitation, and complementation assays showed that PEX10 is required for matrix protein import and that overexpression rescues PEX12 zinc‐finger mutations (PMID:10562279, PMID:10837480). Loss‐of‐function mutations disrupt peroxisomal assembly and correlate with more severe clinical phenotypes.

Integration and Conclusion

Genetic and functional data converge to support a Strong gene‐disease association for PEX10 in PBD6B. The combination of multiple probands with diverse variant types, segregation in families, and concordant mechanistic studies provides robust evidence. PEX10 testing should be included in diagnostic panels for early‐onset autosomal recessive ataxia with cerebellar and multi‐system features.

Key Take-home: PEX10 loss of function underlies PBD6B and genetic testing informs clinical diagnosis, prognosis, and genetic counseling.

References

• Clinical neurology and neurosurgery • 2019 • Ataxia with novel compound heterozygous PEX10 mutations and a literature review of PEX10-related peroxisome biogenesis disorders. PMID:30640048
• Human mutation • 2000 • Phenotype-genotype relationships in PEX10-deficient peroxisome biogenesis disorder patients. PMID:10862081
• Human mutation • 2009 • Identification of novel mutations and sequence variation in the Zellweger syndrome spectrum of peroxisome biogenesis disorders. PMID:19105186
• PloS one • 2025 • Identification of novel compound heterozygous variants in the PEX10 gene in a Han-Chinese family with PEX10-related peroxisome biogenesis disorders. PMID:40267090
• 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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