PEX1 – Peroxisome Biogenesis Disorder

Peroxisome biogenesis disorders (PBDs) are a heterogeneous group of autosomal recessive diseases caused by defective peroxisomal assembly. The PEX1 gene (HGNC:8850) encodes the AAA ATPase peroxin-1, which is essential for peroxisomal matrix protein import. Biallelic loss-of-function and hypomorphic variants in PEX1 underlie complementation group 1 PBDs, representing approximately half of all PBD cases and spanning severe Zellweger syndrome to milder phenotypes such as infantile Refsum and Heimler syndromes (PMID:9398847).

Extensive genetic evidence supports a definitive PEX1–PBD association. In the initial cohort, expression of human PEX1 rescued peroxisomal import in fibroblasts from 30 CG1 probands, with PEX1 mutations identified in each (PMID:9398847). A systematic study of 31 survivors beyond infancy revealed 21 patients harboring PEX1 variants, notably the recurrent missense G843D allele in homozygous or compound heterozygous states, correlating with milder outcomes (PMID:15098231). Multiple case series, including the first Korean Zellweger patient with compound heterozygous c.2034_2035delCA and c.2845C>T (p.Arg949Trp) variants, confirm autosomal recessive inheritance and segregation in parental samples (PMID:21844578).

The PEX1 variant spectrum encompasses at least 200 distinct alleles: >50 missense (e.g., c.2528G>A (p.Gly843Asp)), numerous frameshift, nonsense, splice-site, and deep-intronic changes. The c.2528G>A (p.Gly843Asp) allele accounts for ~50% of CG1 alleles, with hypomorphic activity and genotype–phenotype correlation across diverse populations. Segregation analyses in multiple families firmly establish causality for biallelic PEX1 variants.

Functional assays demonstrate concordant pathogenicity. Fibroblast complementation with wild-type PEX1 restores peroxisomal matrix import, while PEX1-G843D exhibits a deleterious effect on ATPase function and PEX5 stability in vitro (PMID:9398847). Temperature-sensitive PEX1 mutants and a Pex1-G844D knock-in mouse model recapitulate the mild ZSD phenotype and respond to pharmacological chaperones, supporting a loss-of-function mechanism (PMID:24503136). Adult-onset diagnoses illustrate that hypomorphic deep-intronic variants can produce late-onset retinal dystrophy with normal VLCFA levels, identified by RNA-seq and functional rescue of splicing defects (PMID:36293220).

Clinically, PEX1 deficiency manifests with neonatal hypotonia, seizures, craniofacial dysmorphism, hepatomegaly, feeding difficulties, sensorineural hearing loss, pigmentary retinopathy, global developmental delay, and progressive liver dysfunction. Disease severity correlates with the residual activity of PEX1 alleles, enabling genotype-based prognostication.

Key Take-home: Biallelic PEX1 variants cause definitive autosomal recessive peroxisome biogenesis disorders through loss of peroxin-1 function; genetic and functional assays support robust diagnostic, prognostic, and therapeutic decision-making.

References

• Nature genetics • 1997 • Mutations in PEX1 are the most common cause of peroxisome biogenesis disorders. PMID:9398847
• American journal of medical genetics. Part A • 2004 • Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients. PMID:15098231
• Annals of clinical and laboratory science • 2011 • Two novel PEX1 mutations in a patient with Zellweger syndrome: the first Korean case confirmed by biochemical, and molecular evidence. PMID:21844578
• Molecular genetics and metabolism • 2014 • The Pex1-G844D mouse: a model for mild human Zellweger spectrum disorder. PMID:24503136
• International journal of molecular sciences • 2022 • Diagnostic Odyssey in an Adult Patient with Ophthalmologic Abnormalities and Hearing Loss: Contribution of RNA­Seq to the Diagnosis of a PEX1 Deficiency. PMID:36293220

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