Identification of PEX10, the gene defective in complementation group 7 of the peroxisome-biogenesis disorders.
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.
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
D S
DS
Warren
J C
JC
Morrell
H W
HW
Moser
D
D
Valle
S J
SJ
Gould
D000326:Adrenoleukodystrophy / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002107:Caenorhabditis / Q000235:genetics; D002460:Cell Line; D005091:Exons; D005347:Fibroblasts / Q000648:ultrastructure; D005816:Genetic Complementation Test; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008565:Membrane Proteins; D008830:Microbodies / Q000235:genetics; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016366:Open Reading Frames; D000074401:Peroxins; D018901:Peroxisomal Disorders / Q000235:genetics*; D010843:Pichia / Q000235:genetics; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012867:Skin / Q000648:ultrastructure; D014162:Transfection; D044767:Ubiquitin-Protein Ligases; D015211:Zellweger Syndrome / Q000235:genetics
D008565:Membrane Proteins; C492057:PEX10 protein, S cerevisiae; C116156:PEX10 protein, human; D000074401:Peroxins; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; D044767:Ubiquitin-Protein Ligases