PEX1 – Peroxisome Biogenesis Disorder 1B

PEX1 encodes an AAA ATPase essential for peroxisomal matrix protein import. Bi-allelic variants in PEX1 cause peroxisome biogenesis disorder 1B, an autosomal recessive condition within the Zellweger spectrum characterized by global developmental delay, rod-cone dystrophy and sensorineural hearing impairment. Biochemical hallmarks include elevated plasma very-long-chain fatty acids, phytanic and pristanic acids, and deficient dihydroxyacetone phosphate acyltransferase activity in fibroblasts (PMID:26303611).

Inheritance is autosomal recessive, typically in consanguineous or multiplex pedigrees, though few additional affected relatives have been documented. Pathogenic alleles span missense, frameshift, nonsense and splice-site variants. The recurrent missense allele c.2528G>A (p.Gly843Asp) accounts for over 30 % of PEX1 mutations across Zellweger spectrum phenotypes (PMID:11389485). Loss-of-function variants such as c.2097dup (p.Ile700fs) correlate with severe Zellweger syndrome (PMID:10447258).

Case series of 33 unrelated Zellweger spectrum patients identified PEX1 mutations in ~65 % of complementation group 1 cases, with hypomorphic alleles associated with milder neonatal adrenoleukodystrophy and infantile Refsum disease (PMID:16141001, PMID:11389485). In a single infantile Refsum disease patient, homozygous c.2528G>A (p.Gly843Asp) was confirmed by biochemical and molecular testing, guiding dietary intervention that normalized phytanic acid levels (PMID:26303611).

Functional studies demonstrate that wild-type PEX1 expression restores peroxisomal matrix protein import in PEX1-deficient fibroblasts (PMID:9398847). The p.Gly843Asp substitution misfolds at 37 °C, attenuates interaction with PEX6, and can be rescued by PEX6 overexpression in allele-specific assays (PMID:9671729).

A Pex1-G844D knock-in mouse recapitulates key features of mild Zellweger spectrum disorder, including growth retardation, fatty liver cholestasis and photoreceptor degeneration, and responds to chaperone-like compounds that normalize peroxisomal β-oxidation (PMID:24503136).

Together, extensive genetic and experimental data over two decades establish a definitive association between PEX1 and peroxisome biogenesis disorder 1B. Clinical PEX1 testing enables early diagnosis, genotype-phenotype correlation and informs therapeutic development, including chaperone-based strategies.

References

• Nature Genetics • 1997 • Mutations in PEX1 are the most common cause of peroxisome biogenesis disorders. PMID:9398847
• 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 • 1999 • Identification of a common PEX1 mutation in Zellweger syndrome. PMID:10447258
• American Journal of Human Genetics • 2001 • Disorders of peroxisome biogenesis due to mutations in PEX1: phenotypes and PEX1 protein levels. PMID:11389485
• Journal of Medical Genetics • 2005 • Genetic and clinical aspects of Zellweger spectrum patients with PEX1 mutations. PMID:16141001
• Molecular Genetics and Metabolism • 2014 • The Pex1-G844D mouse: a model for mild human Zellweger spectrum disorder. PMID:24503136
• JIMD Reports • 2016 • Infantile Refsum Disease: Influence of Dietary Treatment on Plasma Phytanic Acid Levels. PMID:26303611

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