Alternative titles; symbols
HGNC Approved Gene Symbol: PEX3
Cytogenetic location: 6q24.2 Genomic coordinates (GRCh38) : 6:143,450,805-143,490,616 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q24.2 | ?Peroxisome biogenesis disorder 10B | 617370 | Autosomal recessive | 3 |
| Peroxisome biogenesis disorder 10A (Zellweger) | 614882 | Autosomal recessive | 3 |
Peroxins (PEXs) are proteins that are essential for the assembly of functional peroxisomes. The S. cerevisiae Pex3 protein is a peroxisomal integral membrane protein required for peroxisome biogenesis and integrity. By searching an EST database for sequences similar to the yeast Pichia pastoris Pex3 gene, Kammerer et al. (1998) identified human PEX3 cDNAs. Two of the cDNAs represent alternatively polyadenylated transcripts. The deduced 373-amino acid protein shares 23% and 20% sequence identity with P. pastoris and S. cerevisiae Pex3, respectively. The yeast and human proteins have 2 predicted transmembrane regions in their N-terminal halves. Using immunofluorescence, the authors localized epitope-tagged PEX3 to the peroxisome. Overexpression of PEX3 in mammalian cells led to proliferation of endoplasmic reticulum (ER) membranes, suggesting that the early steps of peroxisome formation may be directed via the ER. Northern blot analysis revealed that PEX3 was expressed as a predominant 2.3-kb mRNA and a 1.6-kb mRNA in all human tissues tested.
Muntau et al. (2000) reported the genomic organization of PEX3, sequencing of the putative promoter region, chromosomal localization, and physical mapping. The gene contains 12 exons and spans approximately 40 kb. They assigned the gene to chromosome 6q23-q24 by fluorescence in situ hybridization.
Sugiura et al. (2017) followed the generation of new peroxisomes within human patient fibroblasts lacking peroxisomes and showed that the essential import receptors Pex3 and Pex14 (601791) 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.
Peroxisome biogenesis disorders, of which several complementation groups have been identified, are subdivided with regard to 2 major dysfunctions: peroxisomal matrix protein import and peroxisomal membrane synthesis. Detectable remnant membrane structures are evident only in the former. Shimozawa et al. (2000) stated that molecular defects had been defined in 10 PEX genes, including 8 related to protein import and 2 related to membrane synthesis. Shimozawa et al. (2000) determined that the human cDNA encoding peroxin-3 rescued the import of both peroxin-3 and the matrix protein in fibroblasts from a Zellweger syndrome patient of complementation group G (614882). The patient was homozygous for a mutation in the PEX3 gene (603164.0001).
Muntau et al. (2000) studied 2 patients assigned to complementation group G of Zellweger syndrome who had been found to display a cellular phenotype characterized by a lack of even residual peroxisomal membrane structures. They identified homozygous PEX3 mutations, each leading to C-terminal truncation of PEX3, in the 2 patients, both of whom suffered from a severe Zellweger syndrome phenotype; see 603164.0001 and 603164.0002.
Ghaedi et al. (2000) studied a patient with Zellweger syndrome of complementation group G and demonstrated a homozygous inactivating mutation in PEX3.
In a 9-year-old boy with peroxisome biogenesis disorder-10B (PBD10B; 617370), Maxit et al. (2017) identified compound heterozygous mutations in the PEX3 gene (R300X, 603164.0003 and G331R, 603164.0004). Functional studies of the variants were not performed. Patient cells showed a mosaic pattern of catalase-positive particles and peroxisomal membrane structures, consistent with the milder clinical phenotype.
Takashima et al. (2022) generated an HEK293 cell model with a biallelic hypomorphic mutation in the PEX3 gene, a 15-bp deletion resulting in deletion of 5 well-conserved amino acids. The cell line showed peroxisomal mosaicism, and analysis of individual cell subclones demonstrated that each subclone could give rise to peroxisomal mosaicism. From a functional standpoint, cells with no or few peroxisomes had a higher amount of very long chain fatty acids compared to cells with a higher number of peroxisomes. In fibroblasts from a patient with infantile Refsum disease and biallelic PEX3 hypomorphic mutations, Takashima et al. (2022) also observed changes in peroxisome content. Takashima et al. (2022) concluded that the number of peroxisomes fluctuates in a cell population with peroxisomal mosaicism and that metabolic function correlates to peroxisome content.
In a patient (patient 1, PBDG-01) with Zellweger syndrome of complementation group G (PBD10A; 614882), Muntau et al. (2000) found homozygosity for a 1-bp insertion, a thymine in exon 7, at nucleotide 543 of the coding region. This frameshift mutation was predicted to result in a truncation of the C-terminal 190 amino acids of the protein. Muntau et al. (2000) noted that the patient showed marked muscular hypotonia at birth. Dysmorphic features included hypertelorism, prominent epicanthic folds, and a high, broad forehead with round face. Seizures developed on day 1 but were controlled with treatment. His condition deteriorated rapidly, with death at age 4 months.
Shimozawa et al. (2000) studied the same patient (G-01) and described the mutation as a homozygous 1-bp insertion at nucleotide 544 at the first position of codon val182, resulting in a change of codon (182-183) and introduction of a termination in codon 184.
Poulos et al. (1995) originally studied this patient (patient 1) and described clinical, pathologic, and biochemical findings.
In a patient (patient 2, PBDG-02) with Zellweger syndrome of complementation group G (PBD10A; 614882), Muntau et al. (2000) found a T-to-G transversion at position -8 of the 3-prime acceptor splice site of intron 10 of the PEX3 gene. This mutation led to deletion of exon 11 and a frameshift, with a premature termination after 3 amino acids, predicting a 56-amino acid C-terminal truncation of the protein. The male infant was cyanotic and markedly hypotonic at birth with absent deep tendon reflexes. He had a prominent midface and downslanting palpebral fissures, ocular hypertelorism, small low-set ears, a prominent nose, and a high-arched palate. The patient died at age 19 days. A brother had been similarly affected and died at age 15 days. Ghaedi et al. (2000) demonstrated the same mutation in a study of material from the same patient.
Poulos et al. (1995) originally studied this patient (patient 2) and described clinical, pathologic, and biochemical findings.
In a 9-year-old boy with peroxisome biogenesis disorder-10B (PBD10B; 617370), Maxit et al. (2017) identified compound heterozygous mutations in the PEX3 gene: a c.898C-T transition (c.898C-T, NM_003630.2), resulting in an arg300-to-ter (R300X) substitution, and a c.991G-A transition, resulting in a gly331-to-arg (G331R; 603164.0004) substitution at a highly conserved residue. Each unaffected parent was heterozygous for 1 of the mutations. Functional studies of the variants were not performed.
For discussion of the c.991G-A transition (c.991G-A, NM_003630.2) in the PEX3 gene, resulting in a gly331-to-arg (G331R) substitution, that was found in compound heterozygous state in a patient with peroxisome biogenesis disorder-10B (PBD10B; 617370) by Maxit et al. (2017), see 603164.0003.
Ghaedi, K., Honsho, M., Shimozawa, N., Suzuki, Y., Kondo, N., Fujiki, Y. PEX3 is the causal gene responsible for peroxisome membrane assembly-defective Zellweger syndrome of complementation group G. Am. J. Hum. Genet. 67: 976-981, 2000. [PubMed: 10968777] [Full Text: https://doi.org/10.1086/303086]
Kammerer, S., Holzinger, A., Welsch, U., Roscher, A. A. Cloning and characterization of the gene encoding the human peroxisomal assembly protein Pex3p. FEBS Lett. 429: 53-60, 1998. [PubMed: 9657383] [Full Text: https://doi.org/10.1016/s0014-5793(98)00557-2]
Maxit, C., Denzler, I., Marchione, D., Agosta, G., Koster, J., Wanders, R. J. A., Ferdinandusse, S., Waterham, H. R. Novel PEX3 gene mutations resulting in a moderate Zellweger spectrum disorder. JIMD Rep. 34: 71-75, 2017. [PubMed: 27557811] [Full Text: https://doi.org/10.1007/8904_2016_10]
Muntau, A. C., Holzinger, A., Mayerhofer, P. U., Gartner, J., Roscher, A. A., Kammerer, S. The human PEX3 gene encoding a peroxisomal assembly protein: genomic organization, positional mapping, and mutation analysis in candidate phenotypes. Biochem. Biophys. Res. Commun. 268: 704-710, 2000. [PubMed: 10679269] [Full Text: https://doi.org/10.1006/bbrc.2000.2193]
Muntau, A. C., Mayerhofer, P. U., Paton, B. C., Kammerer, S., Roscher, A. A. Defective peroxisome membrane synthesis due to mutations in human PEX3 causes Zellweger syndrome, complementation group G. Am. J. Hum. Genet. 67: 967-975, 2000. [PubMed: 10958759] [Full Text: https://doi.org/10.1086/303071]
Poulos, A., Christodoulou, J., Chow, C. W., Goldblatt, J., Paton, B. C., Orii, T., Suzuki, Y., Shimozawa, N. Peroxisomal assembly defects: clinical, pathologic, and biochemical findings in two patients in a newly identified complementation group. J. Pediat. 127: 596-599, 1995. [PubMed: 7562283] [Full Text: https://doi.org/10.1016/s0022-3476(95)70121-4]
Shimozawa, N., Suzuki, Y., Zhang, Z., Imamura, A., Ghaedi, K., Fujiki, Y., Kondo, N. Identification of PEX3 as the gene mutated in a Zellweger syndrome patient lacking peroxisomal remnant structures. Hum. Molec. Genet. 9: 1995-1999, 2000. [PubMed: 10942428] [Full Text: https://doi.org/10.1093/hmg/9.13.1995]
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]
Takashima, S., Fujita, H., Toyoshi, K., Ohba, A., Hirata, Y., Shimozawa, N., Oh-Hashi, K. Hypomorphic mutation of PEX3 with peroxisomal mosaicism reveals the oscillating nature of peroxisome biogenesis coupled with differential metabolic activities. Molec. Genet. Metab. 137: 68-80, 2022. [PubMed: 35932552] [Full Text: https://doi.org/10.1016/j.ymgme.2022.07.008]