Alternative titles; symbols
HGNC Approved Gene Symbol: PEX2
Cytogenetic location: 8q21.13 Genomic coordinates (GRCh38) : 8:76,980,258-77,001,044 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q21.13 | Peroxisome biogenesis disorder 5A (Zellweger) | 614866 | Autosomal recessive | 3 |
| Peroxisome biogenesis disorder 5B | 614867 | Autosomal recessive | 3 |
Using rat PAF1 cDNA to probe a human liver cDNA library, Shimozawa et al. (1992) isolated a cDNA with a 915-bp open reading frame that shares 86% nucleotide identity and 88% deduced amino acid identity with the rat gene. Both sequences encode a protein with 2 highly conserved, putative membrane spanning sequences and 7 cysteine residues in the C-terminal region. Transfection of human PAF1 cDNA corrected the peroxisome assembly defect in the cells of a Japanese girl (M.M.) with Zellweger syndrome (see 214100) but not in cells of other complementation types (Gartner et al., 1992). As predicted by these results, fusion of the patient's fibroblasts with peroxisome-deficient Chinese hamster ovary mutant Z65 cells failed to restore peroxisomes. Fusion of Z65 cells with fibroblasts of other peroxisome biogenesis disorder (PBD; 601539) complementation groups did result in restoration of peroxisomes.
Berteaux-Lecellier et al. (1995) identified a nonmammalian homolog of the PAF1 gene. The discovery was serendipitous, as one would not expect that caryogamy (nuclear fusion) in the filamentous fungus Podospora anserina requires peroxisomes. In filamentous ascomycetes, caryogamy occurs as part of the process leading to meiosis and sexual sporulation. The original car1 mutants were identified in a systematic search for sporulation-deficient mutants (Simonet and Zickler, 1972; Simonet and Zickler, 1978). Berteaux-Lecellier et al. (1995) cloned the car1 gene by complementation. The polypeptide deduced from its sequence showed similarity to the mammalian PAF1 genes: the fungal and the human polypeptides displayed 27% identity over 340 residues; car1 contains the same kind of zinc finger motif as PAF1; and finally, 1 of the 2 putative transmembrane domains of PAF1 is strikingly conserved in the car1 protein. A combination of molecular, physiologic, genetic, and ultrastructural approaches provided evidence that the P. anserina car1 protein is, in fact, a peroxisomal protein.
Using phage and PAC genomic libraries, Biermanns and Gartner (2000) obtained clones containing the full-length PEX2 gene. Northern blot analysis detected ubiquitous expression of a predominant 1.5-kb transcript as well as a 2.4-kb transcript, suggesting that there might be different isoforms; highest expression was detected in skeletal muscle, heart, and pancreas.
Biermanns and Gartner (2000) determined that the PEX2 gene contains 4 exons and spans approximately 17.5 kb. The first 3 exons range from 32 to 110 bp in length, and the entire coding sequence is in the 1,275-bp exon 4. Promoter analysis revealed tissue-specific transcription start sites and features characteristic of a housekeeping gene, but no peroxisomal proliferator response elements were identified.
By fluorescence in situ hybridization, Shimozawa et al. (1993) mapped the PAF1 gene to chromosome 8q21.1; in the full publication, Masuno et al. (1994) used the symbol PXMP3. Biermanns and Gartner (2000) mapped the PEX2 gene to chromosome 8q13-q21 by FISH and localized the mouse Pex2 gene to the proximal region of chromosome 3.
Peroxisome Biogenesis Disorder 5A (Zellweger)
Shimozawa et al. (1992) demonstrated a point mutation (170993.0001) in peroxisome assembly factor-1 (PAF1), a 35-kD peroxisomal membrane protein (PMP35) for which the cDNA had been cloned by Tsukamoto et al. (1991). They had previously shown that this protein corrected the Zellweger-like defect in peroxisome assembly in a peroxisome-deficient Chinese hamster ovary mutant cell line (Z65). From among the 10 or more complementation groups among the peroxisome biogenesis disorders (PBDs; see 214100), they sought one that contained patients with mutations in PAF1. They studied a Japanese girl (M.M.), aged 8 months, with typical clinical findings of Zellweger syndrome (PBD5A; 614866) as well as accumulation of very long chain fatty acids in serum, absence of liver homogenates in all 3 peroxisomal beta-oxidation enzymes, absent peroxisomes in skin fibroblasts, and, at autopsy, macrogyria and polymicrogyria in the brain, hepatosplenomegaly, and many small cysts in the renal cortices bilaterally. Using a mammalian expression vector, Shimozawa et al. (1992) transfected rat PAF1 into patient's cells and found development of peroxisomes, suggesting that the primary defect in patient was in the human ortholog of PAF1.
Using somatic cell fusion for demonstration of complementation, Roscher et al. (1989), Yajima et al. (1992), and Moser et al. (1995) identified more than 10 complementation groups of peroxisome biogenesis disorders indicating that more than 10 genes are required for formation of this organelle. Shimozawa et al. (1993) found that their complementation groups C, E, and F corresponded to groups 3, 2, and 5, respectively, of Brul et al. (1988). Furthermore, complementation group 8 proved to be the same as Japanese group A. Shimozawa et al. (1993) provided a table comparing the complementation groups defined at Gifu University in Japan, Kennedy-Krieger Institute in Baltimore, and Amsterdam University. They pointed out that no obvious relationship between genotype and phenotype was found; the clinical phenotype in a single complementation group could be Zellweger syndrome, neonatal adrenoleukodystrophy, or infantile Refsum disease.
Moser et al. (1995) described a total of 16 complementation groups. Patient M.M. (170993.0001) was found to be in complementation group 10, referred to as group F (Shimozawa et al., 1992), indicating that PAF1 (PEX2) is the gene responsible for this complementation group.
Peroxisome Biogenesis Disorder 5B
In a patient with infantile Refsum disease (IRD; see PBD5B, 614867) from peroxisome biogenesis disorder complementation group 10 (group F), Shimozawa et al. (1999) identified compound heterozygous mutations in the PEX2 gene (R118X, 170993.0001 and E55K, 170993.0002).
In 2 brothers, born of unrelated parents, with PBD5B manifest as isolated cerebellar ataxia, Sevin et al. (2011) identified a homozygous truncating mutation in the PEX2 gene (170993.0006). Patient fibroblasts showed normal peroxisomes and contained catalase, suggesting that the mutant protein is localized correctly in the peroxisomal membrane and retains some activity. Further functional studies were not performed. The report expanded the phenotypic spectrum associated with PEX2 mutations to include mild and isolated autosomal recessive cerebellar ataxia.
Distel et al. (1996) provided a unified nomenclature for peroxisome biogenesis. By the use of genetic approaches in a wide variety of experimental organisms, 13 proteins required for peroxisome biogenesis had been identified in the previous 10 years. Five of these have been shown to be defective in lethal PBDs. However, the diversity of experimental systems had led to a profusion of names for peroxisome assembly genes and proteins. Distel et al. (1996) suggested that proteins involved in peroxisome biogenesis should be designated 'peroxins,' with PEX representing the gene acronym. Even though defects in peroxisomal metabolic enzymes or transcription factors may affect peroxisome proliferation and/or morphology, such proteins should not, they recommended, be included in this group. The proteins and genes were to be numbered by date of published characterization, both for known factors and those identified in the future. In this system, PAF1 becomes PEX2. When necessary, species of origin could be specified by 1-letter abbreviations for genus and species (e.g., hsPEX2).
Chen et al. (2010) reported that Drosophila pex mutants, including Pex2, Pex10 (602859), 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.
Takashima et al. (2021) used TALEN-mediated gene editing to generate a zebrafish pex2 knockout. Only 50% of the fish survived to 2 weeks postfertilization, and only 14% survived to the end of the second month of life. The dying fish had little food in their digestive tracts, indicating abnormal eating. Immunostaining with antibodies against Pmp70 and catalase showed no detectable signal in livers of the mutant fish, indicating complete loss of peroxisomal structures. The mutant fish also developed liver steatosis as embryos. The mutant fish failed to mature sexually; the female fish demonstrated inhibited oogenesis, whereas male fish had mature testes and normal-appearing sperm, but likely failed to develop sexually mature behaviors. Fatty acid analysis demonstrated a distinct fatty acid profile in different tissues from the mutant fish, including brain, liver, and eyes. The livers accumulated saturated very long chain fatty acids and mono- and di-unsaturated fatty acids, whereas brains accumulated ultra very long chain polyunsaturated fatty acids. Transcriptome analysis revealed downregulation of genes involved in gamete development, cellular chemotaxis, muscle contraction, and inflammatory responses in the mutant fish.
Peroxisome Biogenesis Disorder 5A (Zellweger)
By sequencing PAF1 from patient M.M. with Zellweger syndrome (PBD5A; 614866), Shimozawa et al. (1992) found a C-to-T mutation at nucleotide 355 (counting from the first nucleotide of the initiator methionine codon). This resulted in change of codon 118 from CGA (arg) to TGA (stop). When PAF1 cDNA from M.M. was transfected back into her own fibroblasts, correction did not result. Both parents, who were not known to be related but came from the same village, were heterozygous for the mutation. By complementation studies, Shimozawa et al. (1993) demonstrated their group F is the same as complementation group 10 of Moser et al. (1995). They demonstrated, furthermore, that PAF1 transfected into fibroblasts of the Dutch patient reported by Brul et al. (1988) resulted in the formation of normal peroxisomes. Furthermore, they showed that the cells of the Dutch patient were homozygous for the same 355C-T mutation as in the Japanese patient.
In a female infant, born to nonconsanguineous Ashkenazi Jewish parents, with Zellweger syndrome, Gootjes et al. (2004) identified homozygosity for the R119X mutation. Her sister also had Zellweger syndrome. Both sibs died in early infancy.
Peroxisome Biogenesis Disorder 5B
Shimozawa et al. (1999) identified the R119X mutation in compound heterozygosity with a missense mutation (170993.0002) in a patient with infantile Refsum disease (see 614867).
In a 51-year-old Italian man, born of unrelated parents, with PBD5B manifest as childhood-onset cerebellar ataxia and an axonal sensorimotor polyneuropathy, Mignarri et al. (2012) identified compound heterozygosity for the R119X mutation and a 1-bp insertion (c.865_866insA; 170993.0006) in the PEX2 gene. Patient fibroblasts showed mosaicism for a peroxisomal defect, but further functional studies were not performed.
Variant Population Genetics
By screening 2,093 individuals of Ashkenazi Jewish descent from an ultra-Orthodox community through the use of TaqMan genotyping assays, real-time PCR, and allelic discrimination, Fedick et al. (2014) found a carrier frequency of 0.813% (+/-0.3.85%) for the c.355C-T mutation (rs61752123) in the PEX2 gene. They suggested that this mutation be used in screening panels for this population.
In a patient with infantile Refsum disease (IRD; see PBD5B, 614867) from peroxisome biogenesis disorder complementation group 10 (group F), Shimozawa et al. (1999) identified a missense mutation leading to the substitution of lysine in place of glutamic acid at position 55 of the PEX2 gene product (E55K). This mutation was found in compound heterozygosity with R119X (170993.0001). Transfection experiments demonstrated that cells containing the E55K mutation had mosaic activities of peroxisomal function, while those with the nonsense mutation did not. Shimozawa et al. (1999) concluded that allelic heterogeneity affects peroxisomal protein import and functions and regulates the clinical severity in peroxisome biogenesis disorders.
In a male newborn with Zellweger syndrome (PBD5A; 614866), Gootjes et al. (2004) identified a homozygous deletion of 5 basepairs (c.279_283delGAGAT), resulting in a frameshift (Arg94fs98Ter) and termination of the protein before the first transmembrane domain. The patient was the fourth child of a first-cousin union and presented with severe respiratory distress, seizures, and severe hypotonia after delivery. He had polycystic kidneys bilaterally, and visual evoked potentials were absent. Levels of very long chain fatty acids and pipecolic acid were elevated. The boy died at the age of 2 months.
In a male infant, born of consanguineous Moroccan parents, with Zellweger syndrome (PBD5A; 614866), Gootjes et al. (2004) identified a homozygous c.739T-C transition in the PEX2 gene, predicted to result in a cys247-to-arg (C247R) substitution. The newborn had low birth weight for gestational age, severe hypotonia, dysmorphic features, seizures, absent corpus callosum, severe icterus, as well as other features of the disorder. Electron microscopy showed absence of peroxisomes. The boy died at 3 months of age.
In a patient with infantile Refsum disease (PBD5B; 614867), originally reported by Mandel et al. (1994), Gootjes et al. (2004) identified a homozygous c.669G-A transition in the PEX2 gene, resulting in a trp223-to-ter (W223X) substitution between the second transmembrane domain and the zinc finger binding domain. The boy was born to consanguineous Israeli Arab parents. His development was described as normal in infancy, but by the age of 22 months, he had hypotonia, could not walk unassisted, and had cerebellar and vermian atrophy on MRI. The patient continued to deteriorate and died from pneumonia at age 13.
In 2 brothers, born of unrelated parents, with PBD5B (614867) manifest as isolated cerebellar ataxia beginning in the first or second decade, Sevin et al. (2011) identified a homozygous 1-bp insertion (c.865_866insA) in the PEX2 gene, resulting in a frameshift and premature termination (Ser289LysfsTer36). The patient's unaffected mother was heterozygous for the mutation and 2 unaffected sisters did not carry the mutation; paternal DNA was not available. The mutation was not present in a control database. Patient fibroblasts showed normal peroxisomes and contained catalase, suggesting that the mutant protein is localized correctly in the peroxisomal membrane and retains some activity. Further functional studies were not performed. The report expanded the phenotypic spectrum associated with PEX2 mutations to include mild and isolated autosomal recessive cerebellar ataxia.
In a 51-year-old Italian man, born of unrelated parents, with PBD5B manifest as childhood-onset cerebellar ataxia and an axonal sensorimotor polyneuropathy, Mignarri et al. (2012) identified compound heterozygosity for the c.865_866insA mutation and an R119X mutation (170993.0001) in the PEX2 gene. Patient fibroblasts showed mosaicism for a peroxisomal defect, but further functional studies were not performed.
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