PEX1 – Zellweger spectrum disorders

PEX1 encodes a peroxin essential for peroxisomal matrix protein import, and biallelic PEX1 mutations are the most common cause of Zellweger spectrum disorders (ZSD), a severe autosomal recessive peroxisome biogenesis disorder characterized by craniofacial dysmorphism, hypotonia, seizures, and multi-organ dysfunction. Genetic studies across multiple cohorts have identified PEX1 mutations in 37 unrelated ZSD probands (33 probands)(PMID:11389485) and 4 additional probands in complementation group analyses(PMID:10447258), establishing definitive gene–disease validity. Inheritance is autosomal recessive with at least two affected sib pairs reported, confirming segregation of pathogenic alleles in families.

Case series report a spectrum of PEX1 variants including missense, loss-of-function, splice-site, and frameshift alleles, with recurrent founder alleles like c.2097dup (p.Ile700fs) and c.2528G>A (p.Gly843Asp). One widely studied variant is c.2528G>A (p.Gly843Asp), present in ~50% of complementation group 1 patients and correlating with milder phenotypes at permissive temperatures(PMID:9398847). Genotype-phenotype correlations show null alleles associate with classic severe ZSD, whereas hypomorphic missense alleles yield intermediate or late-onset forms.

Functional assays demonstrate that expression of wild-type PEX1 in patient fibroblasts restores peroxisomal import of matrix proteins, confirming loss-of-function pathogenicity(PMID:9398847). The Pex1-G844D knock-in mouse replicates human mild ZSD features including growth retardation and hepatopathy, and peroxisomal β-oxidation can be normalized by chaperone-like compounds in vitro and in vivo(PMID:24503136).

No studies have directly refuted the PEX1–ZSD link; the association is consistent across genetic and mechanistic investigations. Mild late-onset phenotypes may overlap with other peroxisomal disorders, underscoring the need for comprehensive biochemical and molecular testing.

Integration of genetic and functional data confirms PEX1 as a definitive molecular etiology for ZSD, enabling accurate diagnosis, carrier screening, and prognosis prediction. Key take-home: biallelic PEX1 mutations cause autosomal recessive Zellweger spectrum disorders, and variant type predicts clinical severity, supporting targeted genetic counseling and prenatal diagnosis.

References

• Nature Genetics • 1997 • Mutations in PEX1 are the most common cause of peroxisome biogenesis disorders. PMID:9398847
• American Journal of Human Genetics • 2001 • Disorders of peroxisome biogenesis due to mutations in PEX1: phenotypes and PEX1 protein levels. PMID:11389485
• Molecular Genetics and Metabolism • 2014 • The Pex1-G844D mouse: a model for mild human Zellweger spectrum disorder. PMID:24503136

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