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Disorders of peroxisome biogenesis due to mutations in PEX1: phenotypes and PEX1 protein levels

C Walter1, J Gootjes, P A Mooijer

  • 1Institut für Physiologische Chemie, Abteilung für Zellbiochemie, Ruhr-Universität Bochum, Universitätsstrasse 150, 44801 Bochum, Germany.

American Journal of Human Genetics
|June 5, 2001
PubMed

Insights

Mutations in the PEX1 gene cause peroxisome biogenesis disorders (PBDs). Milder PBD phenotypes like NALD and IRD correlate with residual PEX1 protein, often due to the G843D allele, which is temperature-sensitive.

Area of Science:

  • Biochemistry
  • Genetics
  • Cell Biology

Background:

  • Peroxisome biogenesis disorders (PBDs), including Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD), are severe autosomal recessive genetic disorders.
  • These disorders are genetically heterogeneous, with mutations in the PEX1 gene accounting for approximately 65% of cases (complementation group 1).
  • Understanding genotype-phenotype correlations in PEX1-deficient PBDs is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate genotype-phenotype correlations in patients with PEX1-related peroxisome biogenesis disorders.
  • To identify specific PEX1 mutations and their impact on PEX1 protein levels and peroxisomal function.
  • To explore the potential for therapeutic interventions based on the behavior of mutant PEX1 proteins.

Main Methods:

  • Single-strand conformation polymorphism (SSCP) analysis was employed to screen for PEX1 mutations in patients with PBDs.
  • PEX1 protein levels were assessed in patient-derived fibroblasts.
  • Fibroblast cultures were subjected to varying temperatures (e.g., 30°C) to evaluate the stability and function of mutant PEX1 proteins.

Main Results:

  • A complete absence of PEX1 protein was associated with the severe Zellweger syndrome phenotype.
  • Residual PEX1 protein levels were observed in patients with milder phenotypes (NALD, IRD), frequently linked to the common G843D allele.
  • Lowering the culture temperature to 30°C increased PEX1 protein levels and restored peroxisomal function in fibroblasts carrying the G843D mutation, suggesting a temperature-sensitive misfolding defect.

Conclusions:

  • The severity of PEX1-related peroxisome biogenesis disorders correlates with the level of functional PEX1 protein.
  • The G843D missense mutation in PEX1 leads to a misfolded protein that is more stable and functional at reduced temperatures.
  • Identifying factors or mechanisms that enhance mutant PEX1 protein stability is a promising first step toward developing therapeutic strategies for mild PBDs.

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