TY - JOUR
T1 - Identification of PEX10, the gene defective in complementation group 7 of the peroxisome-biogenesis disorders
AU - Warren, Daniel S.
AU - Morrell, James C.
AU - Moser, Hugo W.
AU - Valle, David
AU - Gould, Stephen J.
N1 - Funding Information:
We thank C. Dunbar for advice and technical assistance, S. Subramani for the anti-PMP70 antibodies, A. Moser and D. Gordon for providing the PBD cell lines, and C. Obie for providing RNA and genomic DNA samples. D.S.W. was supported by The Predoctoral Training Program in Human Genetics at The Johns Hopkins University; and D.V. is an Investigator of the Howard Hughes Medical Institute. This work was supported by National Institutes of Health grants DK45787 and HD10891.
PY - 1998/8
Y1 - 1998/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0032231872&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032231872&partnerID=8YFLogxK
U2 - 10.1086/301963
DO - 10.1086/301963
M3 - Article
C2 - 9683594
AN - SCOPUS:0032231872
SN - 0002-9297
VL - 63
SP - 347
EP - 359
JO - American journal of human genetics
JF - American journal of human genetics
IS - 2
ER -