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Identification of PEX10, the gene defective in complementation group 7 of the peroxisome-biogenesis disorders
D S Warren1, J C Morrell, H W Moser
1Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Insights
Peroxisome biogenesis disorders (PBDs) are lethal genetic diseases. Researchers identified mutations in the PEX10 gene, crucial for peroxisomal matrix protein import, in PBD patients, offering insights into disease mechanisms.
Area of Science:
- Cell Biology
- Genetics
- Biochemistry
Background:
- Peroxisome biogenesis disorders (PBDs) are severe, heterogeneous genetic diseases.
- PBDs manifest with neuronal, hepatic, and renal abnormalities, often leading to early death.
- Defective peroxisomal matrix protein import is a shared cellular phenotype in PBDs and yeast pex mutants.
Purpose of the Study:
- To identify the human orthologue of yeast PEX10 and investigate its role in PBDs.
- To analyze PEX10 mutations in patients with complementation group 7 (CG7) PBDs.
- To elucidate the functional consequences of PEX10 deficiency on peroxisome function.
Main Methods:
- Identification and expression of the human PEX10 orthologue.
- Complementation analysis using PBD patient fibroblasts.
- Mutation analysis (splice site, missense, nonsense) of the PEX10 gene in affected individuals.
Main Results:
- Human PEX10 expression rescued peroxisomal matrix protein import in CG7 PBD fibroblasts.
- Mutations in PEX10 were identified in two unrelated CG7 patients.
- Specific PEX10 mutations, including a splice donor site mutation and missense/nonsense mutations, were found in Zellweger syndrome and neonatal adrenoleukodystrophy patients.
Conclusions:
- Loss-of-function mutations in PEX10 cause peroxisome biogenesis disorders.
- PEX10 is essential for the import of peroxisomal matrix proteins.
- Partially functional PEX10 alleles may correlate with milder disease phenotypes.
Abstract:
The peroxisome-biogenesis disorders (PBDs) are a group of genetically heterogeneous, lethal diseases that are characterized by neuronal, hepatic, and renal abnormalities; severe mental retardation; and, in their most severe form, death within the 1st year of life. Cells from all PBD patients exhibit decreased import of one or more classes of peroxisome matrix proteins, a phenotype shared by yeast pex mutants. We identified the human orthologue of yeast PEX10 and observed that its expression rescues peroxisomal matrix-protein import in PBD patients' fibroblasts from complementation group 7 (CG7). In addition, we detected mutations on both copies of PEX10 in two unrelated CG7 patients. A Zellweger syndrome patient, PBD100, was homozygous for a splice donor-site mutation that results in exon skipping and loss of 407 bp from the PEX10 open reading frame. A more mildly affected neonatal adrenoleukodystrophy patient was a compound heterozygote for a missense mutation in the PEX10 zinc-binding domain, H290Q, and for a nonsense mutation, R125ter. Although all three mutations attenuate PEX10 activity, the two alleles detected in the mildly affected patient, PBD052, encode partially functional PEX10 proteins. PEX10-deficient PBD100 cells contain many peroxisomes and import peroxisomal membrane proteins but do not import peroxisomal matrix proteins, indicating that loss of PEX10 has its most pronounced effect on peroxisomal matrix-protein import.