Alternative titles; symbols
HGNC Approved Gene Symbol: PEX13
Cytogenetic location: 2p15 Genomic coordinates (GRCh38) : 2:61,017,720-61,051,990 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p15 | Peroxisome biogenesis disorder 11A (Zellweger) | 614883 | Autosomal recessive | 3 |
| Peroxisome biogenesis disorder 11B | 614885 | Autosomal recessive | 3 |
The PEX13 gene encodes peroxisome biogenesis factor-13, a peroxisomal membrane protein that acts as an essential docking factor for the import of peroxisomal matrix proteins containing the C-terminal peroxisomal uptake-targeting signal PTS1 (Gould et al., 1996).
By studying yeast mutants deficient in import of peroxisomal proteins, Gould et al. (1996) identified a novel integral peroxisomal membrane protein in both yeast and humans that binds the PTS1 receptor via a cytoplasmically oriented SH3 domain. They designated the protein Pex13p (PEX13).
Elgersma et al. (1996) identified the same protein in S. cerevisiae.
Bjorkman et al. (1998) determined that human PEX13 cDNA encodes a deduced 403-residue protein product with a calculated molecular mass of 44.3 kD.
By EST database searching, Fransen et al. (1998) identified a second isoform of PEX13 containing an additional 39 proline-rich amino acids at the N terminus.
Bjorkman et al. (1998) reported that the PEX13 gene spans approximately 11 kb and contains 4 exons, 1 more than previously thought.
By fluorescence in situ hybridization, Bjorkman et al. (1998) mapped the PEX13 gene to chromosome 2p15.
Gould et al. (1996) concluded that PEX13 functions as a docking factor for the predominantly cytoplasmic PTS1 receptor.
Elgersma et al. (1996) showed that a point mutation in the C-terminal SH3 domain of the Pex13p protein inactivated the protein but did not affect its membrane targeting. A 2-hybrid screen with the SH3 domain of Pex13p identified Pex5p (600414), a receptor for proteins with a PTS1 signal as its ligands. Pex13p SH3 interacted specifically with Pex5p in vitro. They found that Pex5p was present mainly in the cytosol and only a small fraction was associated with peroxisomes. Therefore, Elgersma et al. (1996) proposed that Pex13p is a component of the peroxisomal protein import machinery onto which the mobile pex5p receptor docks for the delivery of the selected PTS1 protein. Erdmann and Blobel (1996) showed that cells deficient in Pex13p are unable to import peroxisomal matrix proteins containing PTS1 and, surprisingly, also those containing PTS2.
Shimozawa et al. (1999) reported that the complete human cDNA encoding PEX13 rescued peroxisomal matrix protein import and its assembly in fibroblasts from peroxisome biogenesis disorder patients of complementation group H. They detected mutations in the human PEX13 cDNA in 2 patients of group H (see, e.g., 601789.0001 and 601789.0002).
Liu et al. (1999) characterized the sole representative of complementation group 13 of the PBDs to that time, a patient with neonatal adrenoleukodystrophy (NALD; see 614885). The fibroblasts of this patient (designated PBD222) displayed defects in the import of multiple peroxisomal matrix proteins. However, residual matrix protein import could be detected in the cells from the patient, consistent with the relatively mild phenotype. PEX13 encodes a peroxisomal membrane protein with a cytoplasmically exposed SH3 domain, and Liu et al. (1999) found that expression of human PEX13 restored peroxisomal matrix protein import in cells from patient PBD222. Furthermore, these cells were found to be homozygous for an I326T mutation (601789.0002), which Shimozawa et al. (1999) had independently and simultaneously demonstrated.
In 2 unrelated Saudi patients with Zellweger syndrome (PBD11A; 614883), Al-Dirbashi et al. (2009) identified different homozygous deletions involving the PEX13 gene (601789.0003, 601789.0004).
In a Turkish girl with a peroxisome biogenesis disorder who died at 31 months of age, Krause et al. (2006) identified homozygosity for a T-to-G transversion (c.937T-G) resulting in a substitution of glycine for tryptophan at position 313 (601789.0005).
Maxwell et al. (2003) found that Pex13 null mouse pups exhibited many of the clinical features of Zellweger syndrome, including intrauterine growth retardation, severe hypotonia, failure to feed, and neonatal death. These mice lacked morphologically intact peroxisomes and showed deficient import of matrix proteins containing either type-1 or type-2 peroxisome targeting signals. Biochemical analysis of tissue and cultured skin fibroblasts from these animals indicated severe impairment of peroxisomal fatty acid oxidation and plasmalogen synthesis. The brains of these mice showed disordered lamination in the cerebral cortex, consistent with a neuronal migration defect.
In a patient with a severe Zellweger syndrome phenotype (PBD11A; 614883), Shimozawa et al. (1999) found homozygosity for a nonsense mutation, trp234-to-ter (W234X), which resulted in the loss of not only the SH3 domain but also the putative transmembrane domain of the PEX13 protein.
In the patient originally described by Shimozawa et al. (1998) with neonatal adrenoleukodystrophy (NALD; see PBD11B, 614885), whose fibroblasts showed the temperature-sensitive phenotype, Shimozawa et al. (1999) found homozygosity for a missense mutation, ile326 to thr (I326T), in the SH3 domain of the PEX13 protein. Expression studies of this mutant PEX13 cDNA in a PEX13-defective CHO mutant showed I326T to be a temperature-sensitive mutation and thus suggested that the PEX13 protein with the I326T mutation in the SH3 domain is stable at 30 degrees C but is somewhat unstable at 37 degrees C.
Liu et al. (1999) independently identified homozygosity for the I326T mutation in the cells of patient PBD222, originally described by Shimozawa et al. (1998).
In a Saudi boy, born of consanguineous parents, with Zellweger syndrome (PBD11A; 614883), Al-Dirbashi et al. (2009) identified a homozygous 147-kb deletion that included the PEX13 gene in addition to 70-kb upstream and 45.7-kb downstream regions, predicted to disrupt the hypothetical genes FLJ32312 and KIAA1841. Both deletion breakpoints occurred within Alu repeats. The patient was admitted to the neonatal intensive care unit after birth with severe hypotonia. He had a large anterior fontanel and high forehead. Brain MRI showed polymicrogyria, lissencephaly, and poor myelination, and EEG showed cortical dysfunction and seizure activity. He died at 6 weeks of age of cardiopulmonary arrest. Fibroblast peroxisomes showed a classic 'ghost' appearance due to abnormal protein import, and complementation studies indicated complementation group H (group 13). The deletion was predicted to result in complete loss of PEX13 function.
In a Saudi boy, born of consanguineous parents, with Zellweger syndrome (PBD11A; 614883), Al-Dirbashi et al. (2009) identified a homozygous 14-bp deletion in exon 2 of the PEX13 gene, resulting in a frameshift and premature termination. The patient was admitted to the neonatal intensive care unit shortly after birth because of severe hypotonia, where he showed recurrent apnea, seizures, and elevated liver enzymes. Renal ultrasound showed multiple cysts. He had dysmorphic facies with anteverted nostrils, a depressed nasal bridge, and a large, triangular face. At age 6 months, he showed severe failure to thrive, progressive hepatic dysfunction, and global developmental delay. Fibroblast peroxisomes showed a classic 'ghost' appearance due to abnormal protein import, and complementation studies indicated complementation group H (group 13). The deletion was predicted to result in complete loss of PEX13 function.
In a Turkish patient with a peroxisome biogenesis disorder (PBD11B; 614885) who died at 31 months of age, Krause et al. (2006) identified a homozygous T-to-G transversion at position 937 of the PEX13 cDNA (c.937T-G, NM_002618.2), resulting in a tryptophan-to-glycine substitution at codon 313. The girl exhibited progressive hypotonia and cataracts, but had no dysmorphic features generally observed in classic ZWS.
Al-Dirbashi, O. Y., Shaheen, R., Al-Sayed, M., Al-Dosari, M., Makhseed, N., Abu Safieh, L., Santa, T., Meyer, B. F., Shimozawa, N., Alkuraya, F. S. Zellweger syndrome caused by PEX13 deficiency: report of two novel mutations. Am. J. Med. Genet. 149A: 1219-1223, 2009. [PubMed: 19449432] [Full Text: https://doi.org/10.1002/ajmg.a.32874]
Bjorkman, J., Stetten, G., Moore, C. S., Gould, S. J., Crane, D. I. Genomic structure of PEX13, a candidate peroxisome biogenesis disorder gene. Genomics 54: 521-528, 1998. [PubMed: 9878256] [Full Text: https://doi.org/10.1006/geno.1998.5520]
Elgersma, Y., Kwast, L., Klein, A., Voorn-Brouwer, T., van den Berg, M., Metzig, B., America, T., Tabak, H. F., Distel, B. The SH3 domain of Saccharomyces cerevisiae peroxisomal membrane protein Pex13p functions as a docking site for Pex5p, a mobile receptor for the import of PTS1-containing proteins. J. Cell Biol. 135: 97-109, 1996. [PubMed: 8858166] [Full Text: https://doi.org/10.1083/jcb.135.1.97]
Erdmann, R., Blobel, G. Identification of Pex13p, a peroxisomal membrane receptor for the PTS1 recognition factor. J. Cell Biol. 135: 111-121, 1996. [PubMed: 8858167] [Full Text: https://doi.org/10.1083/jcb.135.1.111]
Fransen, M., Terlecky, S. R., Subramani, S. Identification of a human PTS1 receptor docking protein directly required for peroxisomal protein import. Proc. Nat. Acad. Sci. 95: 8087-8092, 1998. [PubMed: 9653144] [Full Text: https://doi.org/10.1073/pnas.95.14.8087]
Gould, S. J., Kalish, J. E., Morrell, J. C., Bjorkman, J., Urquhart, A. J., Crane, D. I. Pex13p is an SH3 protein of the peroxisome membrane and a docking factor for the predominantly cytoplasmic PTS1 receptor. J. Cell Biol. 135: 85-95, 1996. [PubMed: 8858165] [Full Text: https://doi.org/10.1083/jcb.135.1.85]
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]
Liu, Y., Bjorkman, J., Urquhart, A., Wanders, R. J. A., Crane, D. I., Gould, S. J. PEX13 is mutated in complementation group 13 of the peroxisome- biogenesis disorders. Am. J. Hum. Genet. 65: 621-634, 1999. [PubMed: 10441568] [Full Text: https://doi.org/10.1086/302534]
Maxwell, M., Bjorkman, J., Nguyen, T., Sharp, P., Finnie, J., Paterson, C., Tonks, I., Paton, B. C., Kay, G. F., Crane, D. I. Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads to a Zellweger syndrome phenotype. Molec. Cell. Biol. 23: 5947-5957, 2003. [PubMed: 12897163] [Full Text: https://doi.org/10.1128/MCB.23.16.5947-5957.2003]
Shimozawa, N., Suzuki, Y., Zhang, Z., Imamura, A., Toyama, R., Mukai, S., Fujiki, Y., Tsukamoto, T., Osumi, T., Orii, T., Wanders, R. J. A., Kondo, N. Nonsense and temperature-sensitive mutations in PEX13 are the cause of complementation group H of peroxisome biogenesis disorders. Hum. Molec. Genet. 8: 1077-1083, 1999. [PubMed: 10332040] [Full Text: https://doi.org/10.1093/hmg/8.6.1077]
Shimozawa, N., Suzuki, Y., Zhang, Z., Imamura, A., Tsukamoto, T., Osumi, T., Tateishi, K., Okumoto, K., Fujiki, Y., Orii, T., Barth, P. G., Wanders, R. J. A., Kondo, N. Peroxisome biogenesis disorders: identification of a new complementation group distinct from peroxisome-deficient CHO mutants and not complemented by human PEX 13. Biochem. Biophys. Res. Commun. 243: 368-371, 1998. [PubMed: 9480815] [Full Text: https://doi.org/10.1006/bbrc.1997.8067]