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Identification of PEX10, the gene defective in complementation group 7 of the peroxisome-biogenesis disorders.
- Source :
-
American journal of human genetics [Am J Hum Genet] 1998 Aug; Vol. 63 (2), pp. 347-59. - Publication Year :
- 1998
-
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.
- Subjects :
- Adrenoleukodystrophy genetics
Amino Acid Sequence
Animals
Base Sequence
Caenorhabditis genetics
Cell Line
Exons
Fibroblasts ultrastructure
Genetic Complementation Test
Homozygote
Humans
Infant, Newborn
Membrane Proteins
Microbodies genetics
Molecular Sequence Data
Mutagenesis, Site-Directed
Open Reading Frames
Peroxins
Pichia genetics
Point Mutation
Polymerase Chain Reaction
Receptors, Cytoplasmic and Nuclear biosynthesis
Receptors, Cytoplasmic and Nuclear chemistry
Recombinant Proteins biosynthesis
Recombinant Proteins chemistry
Reverse Transcriptase Polymerase Chain Reaction
Saccharomyces cerevisiae genetics
Sequence Alignment
Sequence Homology, Amino Acid
Skin ultrastructure
Transfection
Ubiquitin-Protein Ligases
Zellweger Syndrome genetics
Peroxisomal Disorders genetics
Receptors, Cytoplasmic and Nuclear genetics
Saccharomyces cerevisiae Proteins
Subjects
Details
- Language :
- English
- ISSN :
- 0002-9297
- Volume :
- 63
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- American journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 9683594
- Full Text :
- https://doi.org/10.1086/301963