Alternative titles; symbols
HGNC Approved Gene Symbol: PEX10
Cytogenetic location: 1p36.32 Genomic coordinates (GRCh38): 1:2,403,974-2,413,827 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.32 | Peroxisome biogenesis disorder 6A (Zellweger) | 614870 | Autosomal recessive | 3 |
| Peroxisome biogenesis disorder 6B | 614871 | Autosomal recessive | 3 |
Warren et al. (1998) identified the human ortholog of yeast PEX10. Okumoto et al. (1998) isolated a human PEX10 cDNA by an expressed sequence tag (EST) homology search of a human DNA database using yeast Pex10 from Hansenula polymorpha, followed by screening of a human liver cDNA library. This cDNA encodes a peroxisomal protein comprising 326 amino acids with 2 putative transmembrane segments and a C3HC4 zinc finger RING motif. Both the N- and C-terminal regions of the PEX10 protein are exposed to the cytosol, as assessed by an expression study of epitope-tagged PEX10 protein.
Peroxisome Biogenesis Disorder 6A (Zellweger)
The peroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous, lethal diseases that are characterized by neuronal, hepatic, and renal abnormalities and severe mental retardation; in their most severe form, death occurs within the first 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. Warren et al. (1998) observed that Pex10 expression rescued peroxisomal matrix-protein import in PBD patients' fibroblasts from complementation group 7 (CG7). In addition, they detected mutations on both copies of PEX10 in 2 unrelated CG7 patients. A Zellweger syndrome (PBD6A; 614870) patient was homozygous for a donor splice site mutation (602859.0001).
Okumoto et al. (1998) showed that PEX10 expression morphologically and biochemically restored peroxisome biogenesis in fibroblasts from Zellweger patients of the complementation group called B in Japan and 7 in the U.S. One patient was found to be homozygous for an inactivating mutation, a 2-bp deletion immediately upstream of the RING motif, which resulted in a frameshift, altering 65 amino acids from the normal (602859.0004). This implied that the C-terminal part, including the RING finger, is required for biologic function of the PEX10 protein. PEX10 cDNA derived from the patient with the mutation was defective in peroxisome-restoring activity when expressed in patient fibroblasts.
Peroxisome Biogenesis Disorder 6B
Warren et al. (1998) found that a patient with PBD6B (614871), a phenotype milder than Zellweger syndrome and more consistent with neonatal adrenoleukodystrophy, was compound heterozygous for a missense mutation (H290Q; 602859.0002) and a nonsense mutation (R125X; 602859.0003) in the PEX10 gene.
In a young woman (PBD687) with a mild form of PBD6B manifest as cerebellar ataxia, previously reported by Clayton et al. (1996), Steinberg et al. (2009) identified compound heterozygous mutations in the PEX10 gene (602859.0007 and 602859.0008). Steinberg et al. (2009) noted the mild and atypical phenotype associated with the peroxisome disorder in this patient. Functional studies of the variants were not performed.
In 2 unrelated patients with PBD6B manifest as childhood-onset cerebellar ataxia and neuropathy, Regal et al. (2010) identified compound heterozygous mutations in the PEX10 gene (602859.0005; 602859.0009-602859.0011). Functional studies of the variants were not performed, but transfection of patient fibroblasts with wildtype PEX10 rescued the mildly abnormal peroxisome phenotype.
Warren et al. (2000) reported phenotype-genotype correlations in patients with PEX10-deficient peroxisome biogenesis disorder. All 4 PEX10-deficient Zellweger syndrome patients were found to have nonsense, frameshift, or splice site mutations that removed large portions of the PEX10 coding region. In contrast, a more mildly affected PEX10-deficient neonatal adrenoleukodystrophy patient expressed a PEX10 allele with a missense mutation, H290Q (602859.0002), affecting the C-terminal zinc-binding domain of the PEX10 product. These results supported the hypothesis that severe loss-of-function mutations in PEX genes cause more severe clinical phenotypes, whereas mildly affected PBD patients have PEX gene mutations that retain residual function.
To quantitate the effects of PEX10 mutations, Warren et al. (2000) used a functional complementation assay. They observed that nonsense and frameshift mutations predicted to delete the C-terminal two-thirds (R125X; 602859.0003) or one-third (704insA) of the protein displayed nearly normal PEX10 activity. They also found that the unexpectedly high PEX10 activity displayed by these cDNAs could be eliminated by removing or mutating segments of the PEX10 cDNA downstream of the mutations. Although these results demonstrated serious flaws in the PEX10 functional complementation assay, they suggested that the C-terminal zinc-binding domain is critical for PEX10 function.
Chen et al. (2010) reported that Drosophila pex mutants, including Pex2 (170993), Pex10, and Pex12 (601758), faithfully recapitulated several key features of human PBD, including impaired peroxisomal protein import, elevated very long chain fatty acid (VLCFA) levels, and growth retardation. Moreover, disruption of pex function resulted in spermatogenesis defects, including spermatocyte cytokinesis failure in Drosophila. Increased VLCFA levels enhanced these spermatogenesis defects whereas reduced VLCFA levels alleviated them. Chen et al. (2010) concluded that regulation of proper VLCFA levels by pex genes is crucial for spermatogenesis.
In a patient (PBD100) with Zellweger syndrome of complementation group 7 (PBD6A; 614870), Warren et al. (1998) found homozygosity for a splice donor-site mutation in the PEX10 gene that resulted in exon skipping and loss of 407 bp from the PEX10 open reading frame. The change was a G-to-A transition in the first position of the splice-donor site in an intron that lies downstream from a 407-bp exon. This mutation corresponded to a C-to-T transition at a CpG dinucleotide on the antisense strand. The homozygous nature of this allele, which destroyed an SnaBI site, was confirmed by restriction enzyme digestion of an amplified genomic DNA fragment spanning the mutation. The PEX10-deficient cells of this patient contained many peroxisomes and imported peroxisomal membrane proteins but did not import peroxisomal matrix proteins, indicating that the loss of PEX10 has its most pronounced effect on peroxisomal matrix protein import.
In a mildly affected patient (PBD052) with neonatal adrenoleukodystrophy (see PBD6B, 614871), Warren et al. (1998) found compound heterozygosity for mutations in the PEX10 gene: a C-G transversion resulting in a his290-to-gln (H290Q) substitution in the zinc-binding domain, and a C-T transition resulting in an arg125-to-ter (R125X; 602859.0003) substitution. The 2 alleles encoded partially functional PEX10 proteins.
For discussion of the arg125-to-ter (R125X) mutation in the PEX10 gene that was found in compound heterozygous state in a patient with neonatal adrenoleukodystrophy (see PBD6B, 614871) by Warren et al. (1998), see 602859.0002.
In cells from a patient with Zellweger syndrome of complementation group 7 (PBD6A; 614870), Okumoto et al. (1998) found homozygosity for an inactivating mutation, a 2-bp deletion at nucleotides 814 and 815 (CT).
The only diagnostic center for PBDs in Japan identified a total of 31 Japanese patients with PBD during the 20 years previous to the report of Shimozawa et al. (2003). There were 27 patients with Zellweger syndrome, including 2 sibs, 3 with neonatal adrenoleukodystrophy (NALD; see 601539), and 1 with rhizomelic chondrodysplasia punctata (RCDP; see 215100). No patient with infantile Refsum disease (IRD; see 601539) had been detected. All 11 patients with Zellweger syndrome of complementation group B had the same mutation, the homozygous 2-bp deletion in PEX10: 814-815delCT. Analysis of single-nucleotide polymorphisms (SNPs) within PEX10 showed that the mutation probably arose once on an ancestral chromosome in the Japanese population.
In a patient (PBD117) with Zellweger syndrome (PBD6A; 614870), Warren et al. (2000) found compound heterozygosity for an A insertion following nucleotide 704 in exon 4 of the PEX10 cDNA and a deletion/insertion/frameshift mutation (602859.0006) in exon 1 of the genome DNA, resulting in loss of nucleotides 13 to 28 of the open reading frame and replacement of these 16 basepairs by a 20-bp insertion. The product of the second allele contained the first 4 amino acids of PEX10 followed by an additional 46 residues and a termination codon; there was no evidence of PEX10 mRNA expression from the second allele.
In an 8.5-year-old boy with PBD6B (614871) manifest as cerebellar ataxia, Regal et al. (2010) identified compound heterozygous mutations in the PEX10 gene: a 1-bp insertion (c.764_765insA), resulting in a frameshift and premature termination, and a c.992G-A transition, resulting in an arg331-to-gln (R331Q; 602859.0009) substitution at a highly conserved residue in the last amino acid in the RING finger domain. Functional studies of the variants were not performed. Regal et al. (2010) stated that the c.764_765insA mutation was the same as the 1-bp insertion mutation identified by Warren et al. (1998) in patient PBD117.
For discussion of the splice site mutation in the PEX10 gene that was found in compound heterozygous state in a patient with Zellweger syndrome (PBD6A; 614870) by Warren et al. (2000), see 602859.0005.
In a young woman (PBD687) with a mild form of peroxisome biogenesis disorder 6B (PBD6B; 614871) manifest mainly as ataxia and nystagmus beginning in early childhood, previously reported by Clayton et al. (1996), Steinberg et al. (2009) identified compound heterozygous mutations in the PEX10 gene: a 1-bp deletion (c.337delC) resulting in a frameshift (Leu113fs) and premature termination at a codon 39 amino acids downstream, inherited from his unaffected father, and a c.890T-C transition, resulting in a leu297-to-pro (L297P; 602859.0008) substitution that apparently occurred de novo on the maternal allele. A c.880A-G transition resulting in a thr294-to-ala (T294A) substitution was also found on the paternal allele. The L297P substitution occurred at a highly conserved residue in the C3HC4 domain. In vitro studies of patient cultured fibroblasts showed no defects in peroxisome metabolism or assembly, but the patient had persistently increased plasma pipecolic acid as well as increased serum bile acid precursors, indicating impaired beta-oxidation of bile acid intermediates and consistent with a generalized defect in peroxisome assembly.
For discussion of the leu297-to-pro (L297P) mutation in the PEX10 gene that was found in compound heterozygous state in a patient with a mild form of peroxisome biogenesis disorder 6B (PBD6B; 614871) by Steinberg et al. (2009), see 602859.0007.
For discussion of the arg331-to-gln (R331Q) mutation in the PEX10 gene that was found in compound heterozygous state in a patient with peroxisome biogenesis disorder 6B (PBD6B; 614871) by Regal et al. (2010), see 602859.0005.
In a 21-year-old male with peroxisome biogenesis disorder 6B (PBD6B; 614871) manifest as childhood-onset cerebellar ataxia, Regal et al. (2010) identified compound heterozygous mutations in the PEX10 gene: a c.2T-C transition, resulting in abolishment of the initiation codon, and a c.790C-T transition, resulting in an arg264-to-ter (R264X; 602859.0011) substitution that would truncate the protein before the RING finger domain. Each unaffected parent was heterozygous for 1 of the mutations.
For discussion of the arg264-to-ter (R264X) mutation in the PEX10 gene that was found in compound heterozygous state in a patient with peroxisome biogenesis disorder 6B (PBD6B; 614871) by Regal et al. (2010), see 602859.0010.
In a Turkish male infant (PBD-HR7) with rapidly progressive Zellweger syndrome (PBD6A; 614870), who died on day 4 of life, Krause et al. (2006) identified a homozygous c.730C-T transition (c.730C-T, NM_002617.3) in the PEX10 gene, predicting an arg244-to-ter (R244X) substitution and either complete or partial lack of the zinc-binding RING finger domain.
Chen, H., Liu, Z., Huang, X. Drosophila models of peroxisomal biogenesis disorder: peroxins are required for spermatogenesis and very-long-chain fatty acid metabolism. Hum. Molec. Genet. 19: 494-505, 2010. [PubMed: 19933170] [Full Text: https://doi.org/10.1093/hmg/ddp518]
Clayton, P. T., Johnson, A. W., Mills, K. A., Lynes, G. W., Wilson, J., Casteels, M., Mannaerts, G. Ataxia associated with increased plasma concentrations of pristanic acid, phytanic acid and C27 bile acids but normal fibroblast branched-chain fatty acid oxidation. J. Inherit. Metab. Dis. 19: 761-768, 1996. [PubMed: 8982949] [Full Text: https://doi.org/10.1007/BF01799170]
Krause, C., Rosewich, H., Thanos, M., Gartner, J. Identification of novel mutations in PEX2, PEX6, PEX10, PEX12, and PEX13 in Zellweger spectrum patients. Hum. Mutat. 27: 1157, 2006. Note: Electronic Article. [PubMed: 17041890] [Full Text: https://doi.org/10.1002/humu.9462]
Okumoto, K., Itoh, R., Shimozawa, N., Suzuki, Y., Tamura, S., Kondo, N., Fujiki, Y. Mutations in PEX10 is the cause of Zellweger peroxisome deficiency syndrome of complementation group B. Hum. Molec. Genet. 7: 1399-1405, 1998. [PubMed: 9700193] [Full Text: https://doi.org/10.1093/hmg/7.9.1399]
Regal, L., Ebberink, M. S., Goemans, N., Wanders, R. J. A., De Meirleir, L., Jaeken, J., Schrooten, M., Van Coster, R., Waterham, H. R. Mutations in PEX10 are a cause of autosomal recessive ataxia. Ann. Neurol. 68: 259-263, 2010. [PubMed: 20695019] [Full Text: https://doi.org/10.1002/ana.22035]
Shimozawa, N., Nagase, T., Takemoto, Y., Ohura, T., Suzuki, Y., Kondo, N. Genetic heterogeneity of peroxisome biogenesis disorders among Japanese patients: evidence for a founder haplotype for the most common PEX10 gene mutation. Am. J. Med. Genet. 120A: 40-43, 2003. [PubMed: 12794690] [Full Text: https://doi.org/10.1002/ajmg.a.20030]
Steinberg, S. J., Snowden, A., Braverman, N. E., Chen, L., Watkins, P. A., Clayton, P. T., Setchell, K. D. R., Heubi, J. E., Raymond, G. V., Moser, A. B., Moser, H. W. A PEX10 defect in a patient with no detectable defect in peroxisome assembly or metabolism in cultured fibroblasts. J. Inherit. Metab. Dis. 32: 109-119, 2009. [PubMed: 19127411] [Full Text: https://doi.org/10.1007/s10545-008-0969-8]
Warren, D. S., Morrell, J. C., Moser, H. W., Valle, D., Gould, S. J. Identification of PEX10, the gene defective in complementation group 7 of the peroxisome-biogenesis disorders. Am. J. Hum. Genet. 63: 347-359, 1998. [PubMed: 9683594] [Full Text: https://doi.org/10.1086/301963]
Warren, D. S., Wolfe, B. D., Gould, S. J. Phenotype-genotype relationships in PEX10-deficient peroxisome biogenesis disorder patients. Hum. Mutat. 15: 509-521, 2000. [PubMed: 10862081] [Full Text: https://doi.org/10.1002/1098-1004(200006)15:6<509::AID-HUMU3>3.0.CO;2-#]