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Phenotype-genotype relationships in peroxisome biogenesis disorders of PEX1-defective complementation group 1 are
S Tamura1, N Matsumoto, A Imamura
1Department of Biology, Faculty of Sciences, Kyushu University Graduate School, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan.
Insights
Peroxisome biogenesis disorders (PBDs) link PEX1 gene mutations to disease severity. Protein stability and Pex1p-Pex6p interaction correlate with temperature sensitivity and clinical outcomes in PBD patients.
Area of Science:
- Biochemistry
- Genetics
- Cell Biology
Background:
- Peroxisome biogenesis disorders (PBDs) are severe genetic diseases.
- Infantile Refsum disease (IRD) exhibits milder symptoms, linked to temperature-sensitive peroxisome assembly.
- PEX1 mutations cause the most common PBDs (CG-E/CG1).
Purpose of the Study:
- Investigate genotype-phenotype relationships in CG1 PBDs.
- Determine the role of PEX1 protein stability and Pex1p-Pex6p interaction in disease manifestation.
- Correlate PEX1 mutations with clinical severity in PBD patients.
Main Methods:
- Analyzed PEX1 protein stability in fibroblasts from IRD and Zellweger syndrome (ZS) patients at different temperatures.
- Assessed Pex1p-Pex6p interaction levels in relation to PEX1 mutations.
- Compared protein behavior between temperature-sensitive (IRD) and non-temperature-sensitive (ZS) PBDs.
Main Results:
- Pex1p with the IRD-associated G843D mutation showed degradation at 37°C but stability at permissive temperatures.
- PEX1 proteins from ZS patients (e.g., L664P mutation) were stable at both temperatures.
- Pex1p-G843D had reduced interaction with Pex6p, while ZS-derived Pex1p showed minimal binding.
Conclusions:
- Pex1p stability correlates with temperature-sensitive peroxisome assembly in IRD.
- Impaired Pex1p-Pex6p interaction contributes to severe PBD phenotypes, like those seen in ZS.
- Understanding these molecular mechanisms can inform PBD diagnosis and treatment strategies.
Abstract:
The peroxisome biogenesis disorders (PBDs), including Zellweger syndrome (ZS), neonatal adrenoleucodystrophy (NALD) and infantile Refsum disease (IRD), are fatal autosomal recessive diseases caused by impaired peroxisome biogenesis, of which 12 genotypes have been reported. ZS patients manifest the severest clinical and biochemical abnormalities, whereas those with NALD and IRD show less severity and the mildest features respectively. We have reported previously that temperature-sensitive peroxisome assembly is responsible for the mildness of the clinical features of IRD. PEX1 is the causative gene for PBDs of complementation group E (CG-E, CG1 in the U.S.A. and Europe), the PBDs of highest incidence, encoding the peroxin Pex1p of the AAA ATPase family. It has been also reported that Pex1p and Pex6p interact with each other. In the present study we investigated phenotype-genotype relationships of CG1 PBDs. Pex1p from IRD such as Pex1p with the most frequently identified mutation at G843D was largely degraded in vivo at 37 degrees C, whereas a normal level of Pex1p was detectable at the permissive temperature. In contrast, PEX1 proteins derived from ZS patients, including proteins with a mutation at L664P or the deletion of residues 634-690, were stably present at both temperatures. Pex1p-G843D interacted with Pex6p at approx. 50% of the level of normal Pex1p, whereas Pex1p from ZS patients mostly showing non-temperature-sensitive peroxisome biogenesis hardly bound to Pex6p. Taking these results together, we consider it most likely that the stability of Pex1p reflects temperature-sensitive peroxisome assembly in IRD fibroblasts. Failure in Pex1p-Pex6p interaction gives rise to more severe abnormalities, such as those manifested by patients with ZS.