Alternative titles; symbols
HGNC Approved Gene Symbol: PEX12
Cytogenetic location: 17q12 Genomic coordinates (GRCh38) : 17:35,574,795-35,578,571 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q12 | Peroxisome biogenesis disorder 3A (Zellweger) | 614859 | Autosomal recessive | 3 |
| Peroxisome biogenesis disorder 3B | 266510 | Autosomal recessive | 3 |
Chang et al. (1997) identified a human ortholog of yeast PEX12 by screening the public database of expressed sequence tags (ESTs) for cDNAs encoding a protein similar to the yeast PEX12 protein. The human gene encodes a predicted 359-amino acid protein with a molecular mass of approximately 40 kD. Although its sequence similarity to yeast PEX12 is limited, the human PEX12 protein is also an integral peroxisomal membrane protein. Like the yeast protein, human peroxin-12 has 2 membrane-spanning domains and a C3HC4 zinc-binding motif extending out into the cytosol. This ring-finger domain is essential for the function of PEX12 (Kalish et al., 1996).
Okumoto and Fujiki (1997) independently cloned a human PEX12 cDNA. Okumoto et al. (1998) determined that the PEX12 protein exposes both N- and C-terminal regions to the cytosol.
Chang et al. (1997) found that PEX12 expression restored peroxisomal protein import in fibroblasts from PBD patients of complementation group 3 (CG3), and they identified frameshift mutations in PEX12 in 2 unrelated CG3 patients (e.g., 601758.0001).
Okumoto and Fujiki (1997) identified a homozygous nonsense mutation in the PEX12 gene (601758.0004) resulting in PEX12 deficiency.
Chang and Gould (1998) demonstrated that all patients from complementation group 3 of the peroxisome biogenesis disorder carry mutations in PEX12. A comparison between PEX12 genotypes and the clinical and cellular phenotypes of the corresponding PBD patients suggested a relatively straightforward relationship between genotype and phenotype in this group of the PBDs, such that the loss of PEX12 function leads to more severe cellular and clinical phenotypes.
Gootjes et al. (2004) reported 5 PBD patients with mutations in the PEX12 gene. Four patients with a severe phenotype had mutations that disrupted the protein and eliminated at least the last zinc-binding domain. One patient with a milder phenotype had an allele that was capable of producing a protein with the zinc-binding domain (see 601758.0009).
Gootjes et al. (2004) reported the biochemical characteristics and molecular basis of a subset of atypical PBD patients. These patients were characterized by abnormal peroxisomal plasma metabolites, but otherwise normal to very mildly abnormal peroxisomal parameters in cultured skin fibroblasts, including a mosaic catalase immunofluorescence pattern in fibroblasts. Since the latter feature made standard complementation analysis impossible, the authors used a novel complementation technique in which fibroblasts were cultured at 40 degrees Celsius, which exacerbates the defect in peroxisome biogenesis. Using this method, they assigned 8 patients to complementation group 3, followed by identification of a single homozygous mutation in the PEX12 gene (601758.0006).
In fibroblasts from a patient (PBD097) with peroxisome biogenesis disorder of complementation group 3 (PBD3A; 614859), Chang et al. (1997) identified compound heterozygosity for a 4-bp insertion after nucleotide 733 of the PEX12 gene and a single T insertion after nucleotide 744 (601758.0002). The 4-bp insertion creates a new Cac8I restriction site.
For discussion of the 1-bp insertion after nucleotide 744 in the PEX12 gene that was found in compound heterozygous state in fibroblasts from a patient (PBD097) with peroxisome biogenesis disorder of complementation group 3 (PBD3A; 614859) by Chang et al. (1997), see 601758.0001. This insertion eliminates an AccI restriction site in the PEX12 gene.
In a patient (PBD040) with peroxisome biogenesis disorder of complementation group 3 (PBD3A; 614859), Chang et al. (1997) identified a 4-bp frameshift mutation in the PEX12 gene. No other PEX12 allele was identified in this patient.
In a patient (PBD3-02) with peroxisome biogenesis disorder of complementation group 3 (PBD3A; 614859), Okumoto and Fujiki (1997) identified homozygosity for an A-to-T transversion in the PEX12 gene, resulting in a termination codon being substituted for lysine at codon 231. Transfection of the patient's PEX12 into a PEX12-deficient cell line did not restore peroxisomes.
In a patient (PBD3-03) with peroxisome biogenesis disorder of complementation group 3 (PBD3A; 614859), Okumoto et al. (1998) identified homozygosity for a 538C-T transition in the PEX12 gene, changing arginine at 180 to a termination codon (R180X). This mutation was incorrectly identified as arg180-to-thr in the abstract.
Chang and Gould (1998) found the R180X mutation in compound heterozygosity in 2 patients with Zellweger syndrome (PBD006, PBD098).
Gootjes et al. (2004) found this mutation in compound heterozygosity with a missense mutation (L317F; 601758.0010) in a patient with a mild form of peroxisome biogenesis disorder of complementation group 3 (PBD3B; 266510). This patient was alive at the age of 22 years.
Gootjes et al. (2004) identified a 959C-T transition in the PEX12 gene, resulting in a ser320-to-phe (S320F) substitution, in 8 PBD patients with atypical features (PBD3B; 266510). The PEX12-S320F patients displayed a relatively mild phenotype compared with the whole PBD spectrum. When compared to mild PEX1-G843D patients (602136.0001), as described by Preuss et al. (2002), they displayed fewer dysmorphic features and ocular abnormalities, although their cerebral and liver abnormalities were similar.
In a patient (PBD099) with a mild form of peroxisome biogenesis disorder of complementation group 3 (PBD3B; 266510), Chang and Gould (1998) identified compound heterozygosity for 2 mutations in the PEX12 gene: a 2-bp deletion (26delCA) early in the coding region and a splice site mutation (601758.0008). PEX12 mRNA present in the patient's cells was derived from only the allele with the 2-bp deletion. The deduced protein product of this mRNA would contain only the first 8 amino acids of the protein, but functional expression studies showed that the mutant PEX12 protein retained significant residual activity, approximately one-seventh that of the wildtype protein. Further analysis showed that the 2-bp mutation resulted in the synthesis of a 29-kD PEX12 protein in vitro, consistent with translation initiation at a downstream internal AUG codon. The authors noted that translation initiation at internal AUG codons may modulate disease phenotypes and should be considered when unexpectedly mild phenotypes result from predicated 'severe' mutations early in the coding region.
For discussion of the splice site mutation in the PEX12 gene that was found in compound heterozygous state in a patient (PBD099) with a mild form of peroxisome biogenesis disorder of complementation group 3 (PBD3B; 266510) by Chang and Gould (1998), see 601758.0007.
In a patient (PEX12-02) with a mild form of peroxisome biogenesis disorder of complementation group 3 (PBD3B; 266510), Gootjes et al. (2004) identified a homozygous 273A-T transversion in the PEX12 gene, resulting in an arg91-to-ser (R91S) substitution in the N terminus. The levels of PEX12 mRNA were relatively normal. Biochemical studies showed that the patient's cells had normal levels of dihydroxyacetonephosphate acyltransferase (DHAPAT) activity. The missense mutation, compared to frameshift or nonsense mutations, is predicted to result in a full-length protein that retains the transmembrane domains and the zinc-binding domain. Gootjes et al. (2004) noted the genotype/phenotype correlation between a milder phenotype and the residual protein activity.
In a patient with a mild form of peroxisome biogenesis disorder of complementation group 3 (PBD3B; 266510), Gootjes et al. (2004) identified compound heterozygosity for 2 mutations in the PEX12 gene: a 949C-T transition, resulting in a leu317-to-phe (L317F) substitution in the zinc-binding domain of the protein, and an R180X (601758.0005) substitution. Although biochemical analyses of the patient's plasma suggested the presence of a peroxisomal disorder, studies of the patient's fibroblasts were normal, suggesting that the defect was organ-specific. Christensen et al. (1990) had previously diagnosed the patient with a deficiency of trihydroxycholestanoyl-CoA oxidase, which Gootjes et al. (2004) excluded as a distinct disease entity.
In a patient (PBD098) with Zellweger syndrome (PBD3A; 614859) who died at the age of 1 month, Chang and Gould (1998) identified compound heterozygosity for a premature termination mutation (R180X; 601758.0005) and a 2-bp deletion in exon 3, c.887_888delTC, that resulted in frameshift after amino acid residue 296 and termination after an additional 11 amino acids. Patient fibroblasts were completely deficient in peroxisomal matrix protein import.
Konkolova et al. (2015) detected the c.887_888delTC mutation in compound heterozygosity with a novel 2-bp duplication (c.767_768dupAT; 601758.0012) in a patient from Slovakia with Zellweger syndrome.
In a patient from Slovakia with Zellweger syndrome (PBD3A; 614859) who died at the age of 23 days, Konkolova et al. (2015) detected a novel 2-bp duplication (c.767_768dupAT) in exon 3 of the PEX12 gene, in compound heterozygosity with a 2-bp deletion (c.887_888delTC; 601758.0011). The duplication resulted in a frameshift after phe256 followed by premature termination after an additional 22 amino acids, truncating the C-terminal zinc-binding domain.
Chang, C.-C., Gould, S. J. Phenotype-genotype relationships in complementation group 3 of the peroxisome-biogenesis disorders. Am. J. Hum. Genet. 63: 1294-1306, 1998. [PubMed: 9792857] [Full Text: https://doi.org/10.1086/302103]
Chang, C.-C., Lee, W.-H., Moser, H., Valle, D., Gould, S. J. Isolation of the human PEX12 gene, mutated in group 3 of the peroxisome biogenesis disorders. Nature Genet. 15: 385-388, 1997. [PubMed: 9090384] [Full Text: https://doi.org/10.1038/ng0497-385]
Christensen, E., Van Eldere, J., Brandt, N. J., Schutgens, R. B. H., Wanders, R. J. A., Eyssen, H. J. A new peroxisomal disorder: di- and trihydroxycholestanaemia due to a presumed trihydroxycholestanoyl-CoA oxidase deficiency. J. Inherit. Metab. Dis. 13: 363-366, 1990. [PubMed: 2122101] [Full Text: https://doi.org/10.1007/BF01799396]
Gootjes, J., Schmohl, F., Mooijer, P. A. W., Dekker, C., Mandel, H., Topcu, M., Huemer, M., von Schutz, M., Marquardt, T., Smeitink, J. A., Waterham, H. R., Wanders, R. J. A. Identification of the molecular defect in patients with peroxisomal mosaicism using a novel method involving culturing of cells at 40 degrees C: implications for other inborn errors of metabolism. Hum. Mutat. 24: 130-139, 2004. [PubMed: 15241794] [Full Text: https://doi.org/10.1002/humu.20062]
Gootjes, J., Schmohl, F., Waterham, H. R., Wanders, R. J. A. Novel mutations in the PEX12 gene of patients with a peroxisome biogenesis disorder. Europ. J. Hum. Genet. 12: 115-120, 2004. [PubMed: 14571262] [Full Text: https://doi.org/10.1038/sj.ejhg.5201090]
Gootjes, J., Skovby, F., Christensen, E., Wanders, R. J. A., Ferdinandusse, S. Reinvestigation of trihydroxycholestanoic acidemia reveals a peroxisome biogenesis disorder. Neurology 62: 2077-2081, 2004. [PubMed: 15184617] [Full Text: https://doi.org/10.1212/01.wnl.0000127576.26352.d1]
Kalish, J. E., Keller, G. A., Morrell, J. C., Mihalik, S. J., Smith, B., Cregg, J. M., Gould, S. J. Characterization of a novel component of the peroxisomal protein import apparatus using fluorescent peroxisomal proteins. EMBO J. 15: 3275-3285, 1996. [PubMed: 8670828]
Konkolova, J., Petrovic, R., Chandoga, J., Halasova, E., Jungova, P., Bohmer, D. A novel mutation in the PEX12 gene causing a peroxisomal biogenesis disorder. Molec. Biol. Rep. 42: 1359-1363, 2015. [PubMed: 26094004] [Full Text: https://doi.org/10.1007/s11033-015-3885-7]
Okumoto, K., Fujiki, Y. PEX12 encodes an integral membrane protein of peroxisomes. (Letter) Nature Genet. 17: 265-266, 1997. [PubMed: 9354782] [Full Text: https://doi.org/10.1038/ng1197-265]
Okumoto, K., Shimozawa, N., Kawai, A., Tamura, S., Tsukamoto, T., Osumi, T., Moser, H., Wanders, R. J. A., Suzuki, Y., Kondo, N., Fujiki, Y. PEX12, the pathogenic gene of group III Zellweger syndrome: DNA cloning by functional complementation on a CHO cell mutant, patient analysis, and characterization of Pex12p. Molec. Cell. Biol. 18: 4324-4336, 1998. [PubMed: 9632816] [Full Text: https://doi.org/10.1128/MCB.18.7.4324]
Preuss, N., Brosius, U., Biermanns, M., Muntau, A. C., Conzelmann, E., Gartner, J. PEX1 mutations in complementation group 1 of Zellweger spectrum patients correlate with severity of disease. Pediat. Res. 51: 706-714, 2002. [PubMed: 12032265] [Full Text: https://doi.org/10.1203/00006450-200206000-00008]