Alternative titles; symbols
HGNC Approved Gene Symbol: PEX26
Cytogenetic location: 22q11.21 Genomic coordinates (GRCh38) : 22:18,077,990-18,105,396 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q11.21 | Peroxisome biogenesis disorder 7A (Zellweger) | 614872 | Autosomal recessive | 3 |
| Peroxisome biogenesis disorder 7B | 614873 | Autosomal recessive | 3 |
Matsumoto et al. (2003) cloned PEX26 from a kidney cDNA library based on its ability to complement a peroxisome biogenesis defect in a mutant Chinese hamster ovary (CHO) cell line. The deduced 305-amino acid protein has a calculated molecular mass of about 34 kD. PEX26 has a C-terminal hydrophobic segment. Epitope-tagged PEX26 was expressed in a punctate pattern that overlapped catalase (115500) staining in transfected CHO cells. Detergent extractions and protease digestion experiments indicated that the N terminus of PEX26 is exposed to the cytosol and the C terminus is exposed to the peroxisome matrix.
By Northern blot analysis, Matsumoto et al. (2003) detected a 4.4-kb PEX26 mRNA transcript in all human tissues examined, with highest expression in the kidney. A smaller 1.8-kb transcript was also detected in several tissues, including kidney and liver.
Matsumoto et al. (2003) found that stable transfection of PEX26 in mutant CHO cells defective in peroxisome biogenesis restored peroxisome biogenesis and catalase activity. By in vitro protein binding assays and coimmunoprecipitation experiments, Matsumoto et al. (2003) determined that PEX26 interacts directly with PEX6 (601498) and indirectly with PEX1 (602136) through PEX6.
The International Radiation Hybrid Mapping Consortium mapped the PEX26 gene to chromosome 22q11.21 (SHGC-32781).
Matsumoto et al. (2003) identified an arg98-to-trp mutation (R98W; 608666.0001) in the PEX26 gene in fibroblasts from a patient with peroxisome biogenesis disorder of complementation group 8 (CG8), resulting in neonatal adrenoleukodystrophy (NALD; see 614873).
Matsumoto et al. (2003) identified mutations in the PEX26 gene in patients with Zellweger syndrome (ZS; see 614872), NALD, and infantile Refsum disease (see 614873) (see 608666.0001-608666.0007). Temperature-sensitive (30 degrees C) functional expression studies of the mutant proteins showed that catalase import was restored in cell lines from the patients with NALD and IRD, but to a much lesser extent in those with Zellweger syndrome, indicating that temperature sensitivity varied inversely with the severity of the clinical phenotype.
Matsumoto et al. (2003) proposed that PEX26 functions as the peroxisomal docking factor for the PEX1/PEX6 heterodimer. Weller et al. (2005) identified previously undescribed PEX26 disease alleles (608666.0008, 608666.0009), localized the PEX6-binding domain to the N-terminal half of the PEX26 protein (amino acids 29-174), and showed that at the cellular level, PEX26 deficiency impairs peroxisomal import of both PTS1- and PTS2-targeted matrix proteins. Weller et al. (2005) also found that PEX26 undergoes alternative splicing to produce several splice forms, including 1 with deletion of exon 5 that maintains frame and encodes an isoform lacking the transmembrane domain of full-length PEX26. Despite its cytosolic location, PEX26 with deleted exon 5 rescues peroxisome biogenesis in PEX26-deficient cells as efficiently as does full-length PEX26. To test their observation that a peroxisomal location is not required for PEX26 function, Weller et al. (2005) made a chimeric protein with PEX26 as its N terminus and the targeting segment of a mitochondrial outer membrane protein (OMP25) at its C terminus. This chimeric protein localized to the mitochondria and directed all detectable PEX6 and a fraction of PEX1 to this extraperoxisomal location; however, the chimeric protein retained the full ability to rescue peroxisome biogenesis in PEX26-deficient cells. On the basis of these observations, Weller et al. (2005) suggested that a peroxisomal localization of PEX26 and PEX6 is not required for their function and that the interaction of PEX6 with PEX1 is dynamic. This model predicted that, once activated in an extraperoxisomal location, PEX1 moves to the peroxisome and completes the function of the PEX1/6 heterodimer.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human PEX26 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In a patient (cell line GM11335) with neonatal adrenoleukodystrophy (NALD; see PBD7B, 614873), Matsumoto et al. (2003) identified a homozygous C-to-T transition at nucleotide 292 of the PEX26 gene, resulting in an arg98-to-trp (R98W) substitution. The mutation rendered PEX26 unstable and less able to participate in PEX6 (601498)-mediated interaction with PEX1 (602136). Transfection of wildtype PEX26 restored peroxisome biogenesis in fibroblasts from this patient. Matsumoto et al. (2003) identified this mutation in homozygosity in a second patient with NALD.
Matsumoto et al. (2003) performed functional expression studies of the R98W mutation, which showed temperature-sensitive (30 degree C) import of catalase and thiolase. They noted that the findings correlated with the milder phenotype in the patient described by Matsumoto et al. (2003).
In a patient (cell line GM16865) with infantile Refsum disease (see 614873), Matsumoto et al. (2003) identified compound heterozygosity for 2 mutations in the PEX26 gene: R98W and a 1-bp insertion, 255insT (608666.0007), resulting in a frameshift introducing a distinct 28-amino acid sequence. Functional coexpression studies of the 2 mutations showed temperature-sensitive (30 degrees C) import of catalase and thiolase.
Weller et al. (2005) pointed out that in the 18 genotyped probands with peroxisome biogenesis disorder of complementation group 8 reported to that time, the R98W mutation accounted for 14 (39%) of the mutant PEX26 genes (10 patients in their study, 4 of whom overlapped with the 7 reported by Matsumoto et al. (2003), and 5 in the report of Steinberg et al. (2004)). The high frequency of R98W may represent a founder effect, as has been described for certain alleles in other peroxisome biogenesis disorder complementation groups (Braverman et al., 1997), or recurrent mutations at a CpG dinucleotide in codon 98 (CGG to TGG).
In 2 unrelated patients (cell lines A-02 and A-06) with Zellweger syndrome (PBD7A; 614872), Matsumoto et al. (2003) identified a homozygous 265G-A transition in the PEX26 gene, resulting in a gly89-to-arg (G89R) substitution. In vitro functional analysis showed that the G89R mutation inactivated the function of PEX26, resulting in weak temperature-sensitive (30 degrees C) import of catalase and thiolase.
In a patient (cell line GM07371) with Zellweger syndrome (PBD7A; 614872), Matsumoto et al. (2003) identified compound heterozygosity for mutations in the PEX26 gene: one allele carried a homozygous 1-bp insertion, T35insC, that resulted in a frameshift introducing a 102-amino acid sequence distinct from normal PEX26, and the other allele carried the T35insC mutation as well as a 147-bp deletion of nucleotides 668-814 resulting in deletion of amino acids 223-271 (del223-271). Functional expression studies of the 35insC mutation showed almost normal catalase and thiolase import. Coexpression studies of the complex allele showed weak temperature-sensitive (30 degree C) import of catalase.
For discussion of an allele containing a 1-bp insertion in the PEX26 gene (T35insC) in cis with a 147-bp deletion in the PEX26 gene that was found in compound heterozygous state in a patient (cell line GM07371) with Zellweger syndrome (PBD7A; 614872) by Matsumoto et al. (2003), see 608666.0003.
In a patient (cell line GM08771) with infantile Refsum disease (see PBD7B, 614873), Matsumoto et al. (2003) identified compound heterozygosity for 2 mutations in the PEX26 gene: a 2T-C transition, resulting in a met1-to-thr (M1T) substitution in the initiator met residue, and a 134T-C transition, resulting in a leu45-to-pro (L45P; 608666.0006) substitution. Functional expression studies showed that the M1T mutation allowed some catalase and thiolase import, whereas the L45P mutation had virtually no temperature-sensitive (30 degrees C) import. Coexpression of the 2 mutations resulted in temperature-sensitive import, corresponding to the milder phenotype.
For discussion of leu45-to-pro (L45P) mutation in the PEX26 gene that was found in compound heterozygous state in a patient (cell line GM08771) with infantile Refsum disease (see PBD7B, 614873) by Matsumoto et al. (2003), see 608666.0005.
For discussion of a 1-bp insertion in the PEX26 gene that was found in compound heterozygous state in a patient (cell line GM16865) with infantile Refsum disease (see PBD7B, 614873) by Matsumoto et al. (2003), see 608666.0001.
In a proband with a Zellweger syndrome phenotype (PBD7A; 614872), Weller et al. (2005) identified a G-to-T transversion at position 1 of the splice donor site of intron 2 of the PEX26 gene, 230+1G-T, resulting in a frameshift at codon 77 and premature termination.
In a patient with a Zellweger syndrome phenotype (PBD7A; 614872), Weller et al. (2005) identified compound heterozygosity for mutations in the PEX26 gene: arg98 to trp (R98W; 608666.0001) and a 1-bp insertion, 254insT, which resulted in a frameshift and premature termination.
In an infant boy with Zellweger syndrome (PBD7A; 614872), the child of healthy first-cousin Saudi parents, Al-Sayed et al. (2007) detected homozygosity for a c.296G-A transition in the PEX26 cDNA that resulted in a trp99-to-ter amino acid substitution (W99X). The patient had typical features of Zellweger syndrome and was one of 4 affected sibs, all of whom died around the age of 4 months.
Al-Sayed, M., Al-Hassan, S., Rashed, M., Qeba, M., Coskun, S. Preimplantation genetic diagnosis for Zellweger syndrome. Fertil. Steril. 87: 1468: e1-e3, 2007. Note: Electronic Article. [PubMed: 17336976] [Full Text: https://doi.org/10.1016/j.fertnstert.2006.09.014]
Braverman, N., Steel, G., Obie, C., Moser, A., Moser, H., Gould, S. J., Valle, D. Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata. Nature Genet. 15: 369-376, 1997. [PubMed: 9090381] [Full Text: https://doi.org/10.1038/ng0497-369]
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Matsumoto, N., Tamura, S., Fujiki, Y. The pathogenic peroxin Pex26p recruits the Pex1p-Pex6p AAA ATPase complexes to peroxisomes. Nature Cell Biol. 5: 454-460, 2003. [PubMed: 12717447] [Full Text: https://doi.org/10.1038/ncb982]
Matsumoto, N., Tamura, S., Furuki, S., Miyata, N., Moser, A., Shimozawa, N., Moser, H. W., Suzuki, Y., Kondo, N., Fujiki, Y. Mutations in novel peroxin gene PEX26 that cause peroxisome-biogenesis disorders of complementation group 8 provide a genotype-phenotype correlation. Am. J. Hum. Genet. 73: 233-246, 2003. [PubMed: 12851857] [Full Text: https://doi.org/10.1086/377004]
Steinberg, S., Chen, L., Wei, L., Moser, A., Moser, H., Cutting, G., Braverman, N. The PEX gene screen: molecular diagnosis of peroxisome biogenesis disorders in the Zellweger syndrome spectrum. Molec. Genet. Metab. 83: 252-263, 2004. [PubMed: 15542397] [Full Text: https://doi.org/10.1016/j.ymgme.2004.08.008]
Weller, S., Cajigas, I., Morrell, J., Obie, C., Steel, G., Gould, S. J., Valle, D. Alternative splicing suggests extended function of PEX26 in peroxisome biogenesis. Am. J. Hum. Genet. 76: 987-1007, 2005. [PubMed: 15858711] [Full Text: https://doi.org/10.1086/430637]