Alternative titles; symbols
HGNC Approved Gene Symbol: PEX14
Cytogenetic location: 1p36.22 Genomic coordinates (GRCh38): 1:10,474,950-10,630,758 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.22 | Peroxisome biogenesis disorder 13A (Zellweger) | 614887 | Autosomal recessive | 3 |
Working with Saccharomyces cerevisiae, Albertini et al. (1997) described peroxin-14 (PEX14), the first membrane-bound peroxisomal protein that binds to the peroxisomal type-2 targeting signal (PTS2) receptor, PEX7 (601757). Thus, the PEX14 protein may represent the functional docking site for PTS2-dependent protein import to the peroxisome. In addition to the interaction with the PTS2 receptor, PEX14 protein was found to interact with PEX5 protein (600414), the PTS1 receptor. This observation suggested the overlapping of 2 import pathways, with PEX14 being the point of convergence. Moreover, PEX14 also interacted with 2 other membrane-bound peroxins, including the SH3 domain protein PEX13 (601789), the putative docking protein for PTS1-dependent protein import. Albertini et al. (1997) proposed that these 3 peroxins are components of a common translocation machinery.
Using yeast Pex14 sequences to probe EST databases, Fransen et al. (1998) identified a cDNA encoding PEX14. The deduced 377-amino acid protein contains a nonmembrane-spanning hydrophobic region, a coiled-coil region, and a charged, acidic C terminus; it has no class II SH3-binding motif. Western blot analysis showed expression of a 57-kD protein.
By searching an EST database using S. cerevisiae Pex14 as query, Will et al. (1999) identified a cDNA encoding PEX14 in a breast cell library. The deduced protein contains 2 conserved coiled-coil region and has a calculated molecular mass of about 41 kD. The human and yeast proteins share 26% identity. Northern blot analysis revealed expression of a 2.1-kb transcript in all tissues examined. Western blot analysis of human fibroblast and in vitro translated protein revealed an apparent molecular mass of about 55 kD, which may reflect its high content of acidic amino acids. Immunofluorescence microscopy revealed colocalization with peroxisomal catalase. PEX14 was found in the particulate fraction of fractionated cells and resisted salt or alkali extraction, suggesting that it is an integral membrane protein. Protease protection assays indicated that the C terminus is cytosolic and that the N terminus likely protrudes into the peroxisomal lumen.
Gavva et al. (2002) identified PEX14, which they called NAPP2, as a protein in an erythroleukemia expression library that interacted with nuclear factor erythroid-2 (NFE2; 601490). Northern blot analysis revealed a transcript of about 2 kb expressed in all cell lines tested.
Ligand blot analysis by Fransen et al. (1998) determined that PEX14 binds to both the PTS1 receptor (PEX5) and weakly with the SH3 domain of PEX13. Biochemical analysis indicated that PEX14 is required for the import of PTS1-containing proteins into peroxisomes.
Will et al. (1999) found that Pex14 deficiency in S. cerevisiae could not be rescued by expression of human PEX14, indicating that the proteins are not functionally interchangeable. Overexpression of PEX14 in normal skin fibroblasts led to the decoration of tubular structures and mislocalization of peroxisomal catalase to the cytosol. Unlike the findings in yeast, PEX14 did not form homooligomers or interact with PTS2 receptor or PEX13.
By in vitro binding assays of truncated recombinant proteins, Gavva et al. (2002) found that interaction between PEX14 and NFE2 occurs through the N-terminal 203 amino acids of PEX14 and the N-terminal 114 amino acids of NFE2. Expression of PEX14 inhibited NFE2-directed transcriptional activation. PEX14 also functioned as a corepressor and interacted specifically with HDAC1 (601241), but not with HDAC2 (605164) or HDAC3 (605166).
Sugiura et al. (2017) followed the generation of new peroxisomes within human patient fibroblasts lacking peroxisomes and showed that the essential import receptors Pex3 (603164) and Pex14 target mitochondria, where they are selectively released into vesicular pre-peroxisomal structures. Maturation of pre-peroxisomes containing Pex3 and Pex14 requires fusion with endoplasmic reticulum-derived vesicles carrying Pex16 (603360), thereby providing full import competence. Sugiura et al. (2017) concluded that their findings demonstrated the hybrid nature of newly born peroxisomes, expanding their functional links to mitochondria.
By FISH, Gavva et al. (2002) mapped the PEX14 gene to chromosome 1p36.
In a patient with Zellweger syndrome (PBD13A; 614887), Shimozawa et al. (2004) identified a gln185-to-ter mutation in the PEX14 gene (Q185X; 601791.0001). Although PEX14 mutants had been identified in yeast and in Chinese hamster ovary (CHO) cells, this was said to be the first reported case of human PEX14 deficiency. Shimozawa et al. (2004) stated that PEX14 is a member of the complementation group of peroxisome biogenesis disorders, and designated it complementation group K. PEX14 rescued the import of a PTS1-dependent as well as a PTS2-dependent protein into the peroxisomes in fibroblasts from the patient. The patient's fibroblasts lacked PEX14, as determined by immunocytochemical analysis.
In an infant with Zellweger syndrome (PBD13A; 614887), Shimozawa et al. (2004) identified a homozygous 553C-T transition in the PEX14 gene, resulting in a gln185-to-ter (Q185X) substitution in a putative coiled-coil region of the protein. At birth the patient showed typical craniofacial dysmorphia of Zellweger syndrome, including large open fontanels, high forehead, flat occiput, low/broad nasal bridge, and micrognathia, as well as neurologic abnormalities including hypotonia. Plasma analysis showed elevated very long chain fatty acids (VLCFA) and di- and trihydroxycholestanoic acid, and a normal phytanic acid level. Erythrocyte plasmalogens were undetectable. The patient died at 10 days of age.
In a Pakistani patient with Zellweger syndrome (PBD13A; 614887), born of related parents, Huybrechts et al. (2008) identified a homozygous 41-kb deletion in the PEX14 gene, resulting in the deletion of exon 3, frameshift, and premature protein truncation. Cultured skin fibroblasts from the patient showed absence of PEX14 protein and absence of normal peroxisomes. The patient had severe cholestasis and hepatomegaly, neuronal migration defect, and progressive hypotonia.
Albertini, M., Rehling, P., Erdmann, R., Girzalsky, W., Kiel, J. A. K.. W., Veenhuis, M., Kunau, W.-H. Pex14p, a peroxisomal membrane protein binding both receptors of the two PTS-dependent import pathways. Cell 89: 83-92, 1997. [PubMed: 9094717] [Full Text: https://doi.org/10.1016/s0092-8674(00)80185-3]
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]
Gavva, N. R., Wen, S.-C., Daftari, P., Moniwa, M., Yang, W.-M., Yang-Feng, L.-P. T., Seto, E., Davie, J. R., Shen, C.-K. J. NAPP2, a peroxisomal membrane protein, is also a transcriptional corepressor. Genomics 79: 423-431, 2002. [PubMed: 11863372] [Full Text: https://doi.org/10.1006/geno.2002.6714]
Huybrechts, S. J., Van Veldhoven, P. P., Hoffman, I., Zeevaert, R., de Vos, R., Demaerel, P., Brams, M., Jaeken, J., Fransen, M., Cassiman, D. Identification of a novel PEX14 mutation in Zellweger syndrome. (Letter) J. Med. Genet. 45: 376-383, 2008. [PubMed: 18285423] [Full Text: https://doi.org/10.1136/jmg.2007.056697]
Shimozawa, N., Tsukamoto, T., Nagase, T., Takemoto, Y., Koyama, N., Suzuki, Y., Komori, M., Osumi, T., Jeannette, G., Wanders, R. J. A., Kondo, N. Identification of a new complementation group of the peroxisome biogenesis disorders and PEX14 as the mutated gene. Hum. Mutat. 23: 552-558, 2004. [PubMed: 15146459] [Full Text: https://doi.org/10.1002/humu.20032]
Sugiura, A., Mattie, S., Prudent, J., McBride, H. M. Newly born peroxisomes are a hybrid of mitochondrial and ER-derived pre-peroxisomes. Nature 542: 251-254, 2017. [PubMed: 28146471] [Full Text: https://doi.org/10.1038/nature21375]
Will, G. K., Soukupova, M., Hong, X., Erdmann, K. S., Kiel, J. A. K. W., Dodt, G., Kunau, W.-H., Erdmann, R. Identification and characterization of the human orthologue of yeast Pex14p. Molec. Cell. Biol. 19: 2265-2277, 1999. [PubMed: 10022913] [Full Text: https://doi.org/10.1128/MCB.19.3.2265]