Alternative titles; symbols
HGNC Approved Gene Symbol: PEX1
SNOMEDCT: 238062008; ICD10CM: G60.1;
Cytogenetic location: 7q21.2 Genomic coordinates (GRCh38): 7:92,487,025-92,528,520 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q21.2 | Heimler syndrome 1 | 234580 | Autosomal recessive | 3 |
| Peroxisome biogenesis disorder 1A (Zellweger) | 214100 | Autosomal recessive | 3 | |
| Peroxisome biogenesis disorder 1B (NALD/IRD) | 601539 | Autosomal recessive | 3 |
Reuber et al. (1997) and Portsteffen et al. (1997) identified the human ortholog of yeast PEX1, a gene required for peroxisomal matrix protein import. The gene encodes a 147-kD member of the AAA protein family (ATPases associated with diverse cellular activities).
By functional complementation of peroxisome deficiency of a mutant Chinese hamster ovary (CHO) cell line, ZP107, transformed with peroxisome targeting signal type 1-tagged 'enhanced' green fluorescent protein, Tamura et al. (1998) isolated a human PEX1 cDNA. This cDNA encoded a hydrophilic protein comprising 1,283 amino acids, with high homology to the AAA-type ATPase family. A stable transformant of ZP107 with human PEX1 was morphologically and biochemically restored for peroxisome biogenesis.
Portsteffen et al. (1997) detected 24 exons in the human PEX1 gene.
By computer-based 'homology probing' using the yeast sequence to screen a database of expressed sequence tags (dbEST) for human cDNA clones, Portsteffen et al. (1997) found a contig sequence localized to 7q21-q22 that exactly matched their cDNA. They identified the human PEX1 homolog and characterized its exon/intron structure.
Peroxisome Biogenesis Disorders 1A and 1B
Reuber et al. (1997) found that expression of human PEX1 restored peroxisomal protein import in fibroblasts from 30 patients with peroxisomal biogenesis disorders of complementation group 1 (CG1; see PBD1A, 214100). Additionally, they detected PEX1 mutations in multiple CG1 probands. A common PEX1 allele, gly843-to-asp (G843D; 602136.0001), was present in approximately half of the CG1 patients and was shown to have a deleterious effect on PEX1 activity. Phenotypic analysis of PEX1-deficient cells revealed severe defects in peroxisomal matrix protein import and destabilization of PEX5 (600414), the receptor for the type 1 peroxisomal targeting signal, even though peroxisomes were present in these cells and capable of importing peroxisomal membrane proteins. These data demonstrated an important role for PEX1 in peroxisome biogenesis and suggested that mutations in PEX1 are the most common cause of the peroxisomal biogenesis disorders (see 601539). Homozygosity for the G843D mutation was found in patients with peroxisome biogenesis disorder-1B (PBD1B; 601539), including at least 1 individual exhibiting neonatal adrenoleukodystrophy (NALD) as well as several cases of infantile Refsum disease (IRD). Heterozygosity for the G843D mutation (with other alleles not characterized) was found in cases of NALD, IRD, and Zellweger syndrome (ZS; 214100) (Reuber et al., 1997). These 3 disorders appeared to represent a continuum of clinical features that are most severe in ZS, milder in NALD, and least severe in IRD.
Portsteffen et al. (1997) identified 3 mutant alleles in CG1 patients, including the G843D mutation, which was found in homozygosity in 1 patient and heterozygosity in another.
Tamura et al. (1998) demonstrated that human PEX1 expression restored peroxisomal protein import in fibroblasts from 3 patients with Zellweger syndrome and neonatal adrenoleukodystrophy of complementation group 1, which is the peroxisome biogenesis disorder (PBD) of highest incidence. Tamura et al. (1998) found that a patient with Zellweger syndrome was compound heterozygous for inactivating mutations of the PEX1 gene (602136.0002, 602136.0003). The cDNAs corresponding to these PEX1 mutations were defective in peroxisome-restoring activity when expressed in the patient's fibroblasts as well as in ZP107 cells. This method of identifying PEX1 cDNA complements that used by Reuber et al. (1997) and Portsteffen et al. (1997), who isolated the human PEX1 gene by a homology search of a human EST database using a yeast PEX1 sequence. All 3 studies demonstrated unequivocally that PEX1 is the causative gene for complementation group 1 peroxisomal disorders.
In fibroblasts from all CG1 infantile Refsum disease (IRD) patients examined, Imamura et al. (1998) found that peroxisomes were morphologically and biochemically formed at 30 degrees centigrade but not at 37 degrees centigrade; on the other hand, almost no peroxisomes were seen in Zellweger syndrome and neonatal adrenoleukodystrophy cells, even at 30 degrees centigrade. The mutation G843D (602136.0001) was found in the PEX1 allele of most CG1 IRD patients. The mutant PEX1 G843D gave rise to the same temperature-sensitive phenotype on CG1 CHO cell mutants upon transfection. Collectively, these results demonstrated temperature-sensitive peroxisome assembly to be responsible for the mildness of the clinical features of PEX1-defective IRD of complementation group 1. Imamura et al. (1998) suggested that the severity of peroxisome biogenesis disorder can be prognosticated by examining the temperature-sensitive complementation of peroxisomes in patient fibroblasts. This prognostic tool may encourage pediatricians to treat the milder PBD variants with therapies such as an oral administration of docosahexaenoic acid.
Collins and Gould (1999) analyzed all 24 exons of the PEX1 gene in 4 patients with CG1 Zellweger syndrome, including 2 patients in whom Gartner et al. (1992) had found variants in the PMP70 gene (170995.0001, 170995.0002). PEX1 mutations were detected in all 4 patients, including a 1-bp insertion (2097insT; 602136.0004) in exon 13 that was present in 3 of the 4 patients. Screening for the 2097insT mutation in 32 additional CG1 patients revealed 3 who were homozygous and 12 who were heterozygous for the insertion. Collins and Gould (1999) noted that in contrast to the other common PEX1 mutation, G843D, which is associated with a trend toward the mild end of the ZS phenotypic spectrum, this second common PEX1 mutation is associated with severe phenotypes.
Mutations in PEX1 account for approximately 65% of patients with PBDs. Walter et al. (2001) found that complete lack of PEX1 protein is associated with severe Zellweger syndrome; however, residual amounts of PEX1 protein were found in patients with the milder phenotypes neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD). Most of the IRD patients carried at least 1 copy of the common G843D allele. When patient fibroblasts harboring this allele were grown at 30 degrees centigrade, a 2- to 3-fold increase in PEX1 protein levels was observed, associated with the recovery of peroxisomal function. This suggested that the G843D missense mutation results in a misfolded protein, which is more stable at lower temperatures. Walter et al. (2001) concluded that their search for the factors and/or mechanisms that determine the stability of mutant PEX1 proteins can be a first step in the development of therapeutic strategies for patients with mild PBDs.
In the subgroup of PBD patients with ZS, NALD, and IRD, more than half have mutations in the PEX1 gene. Maxwell et al. (2002) identified 5 novel mutations in an Australasian cohort of PEX1-deficient PBD patients, including a frameshift mutation in exon 18 (602136.0005) that was present in moderately high frequency (approximately 10% of alleles).
Majewski et al. (2011) identified biallelic mutations in the PEX1 gene in 2 patients. Patient 1 was a 28-year-old woman with PBD1B who had normal cognition and a history of Leber congenital amaurosis (LCA; see 204000). She was homozygous for the common G843D mutation (602136.0001). Patient 2 was an infant with PBD1A who presented with LCA at 9 months of age and had developmental delay, hypotonia, and seizures at 20 months of age. She was compound heterozygous for the G843D mutation and a 1-bp insertion (c.2098insT; 602136.0010).
Heimler Syndrome 1
In affected individuals from 4 unrelated families with sensorineural hearing loss, enamel hypoplasia, and nail defects (HMLR1; 234580), Ratbi et al. (2015) identified biallelic mutations in the PEX1 gene (602136.0004 and 602136.0006-602136.0009). The authors noted that in contrast to patients with PBDs at the severe end of the clinical spectrum, these patients showed no identifiable dysmorphic or additional neurologic features. Complementation assays in PEX1-null cells transfected with variants from patients with Heimler syndrome-1 demonstrated that all affected individuals had at least 1 PEX variant with residual activity in peroxisomal biogenesis.
Maxwell et al. (2002) found a close correlation between cellular phenotype, disease severity, and PEX1 genotype in an Australasian cohort of PEX1-deficient PBD patients. Preuss et al. (2002) also found a close correlation between PEX1 genotype and age of survival in 16 well-documented Zellweger spectrum patients, which supported the usefulness of determining the exact PEX1 mutations in patients. Missense mutations caused milder disease, while insertions, deletions, and nonsense mutations were associated with severe clinical disease.
In 21 of 31 patients with PBDs, Poll-The et al. (2004) identified mutations in the PEX1 gene. The most common mutations were G843D (602136.0001) and 2097insT (602136.0004), which were associated with mild and severe Zellweger syndrome, respectively. Patients homozygous for G843D tended to have a better developmental outcome than did patients compound heterozygous for the 2 mutations. However, there were exceptions, suggesting that unknown factors influence the ultimate phenotype.
In a study of 168 Zellweger spectrum patients, including 33 of their own, Rosewich et al. (2005) found that the G843D and 2097insT mutations accounted for over 80% of all abnormal PEX1 alleles. Most of the mutations were distributed over the 2 AAA cassettes with the 2 functional protein domains, D1 and D2, and the highly conserved Walker motifs. PEX1 mutations could be divided into 2 classes: class I mutations led to residual PEX1 protein levels and function and a milder phenotype; class II mutations almost abolished PEX1 protein levels and function, resulting in a severe phenotype. Patients who were compound heterozygous for a class I and a class II mutation had an intermediate phenotype.
Crane et al. (2005) provided a detailed review of the mutations identified in the PEX1 gene. Mutations that produce premature termination codons are distributed throughout the PEX1 gene, whereas the majority of missense mutations segregate with the 2 essential AAA domains of the PEX1 protein.
In patients with peroxisome biogenesis disorder-1B (PBD1B; 601539), including at least 1 individual exhibiting neonatal adrenoleukodystrophy (NALD) as well as several cases of infantile Refsum disease (IRD), Reuber et al. (1997) identified homozygosity for a gly843-to-asp (G843D) substitution in the PEX1 gene. In addition, the mutation was found in heterozygous state in cases of NALD, IRD, and Zellweger syndrome (PBD1A; 214100), with the other alleles uncharacterized. Functional analysis in patient fibroblasts suggested that the G843D mutant was only about 15% as active as wildtype PEX1. Portsteffen et al. (1997) also identified this mutation in homozygous and heterozygous state in patients with peroxisome biogenesis disorders of complementation group 1.
Among 23 German patients with peroxisomal biogenesis disorder of complementation group 1, Gartner et al. (1999) found that 8 were either homozygous or heterozygous for a c.2528G-A transition in exon 15 of PEX1, producing a G843D amino acid substitution.
In a 28-year-old woman (patient 1) with PBD1B, Majewski et al. (2011) identified homozygosity for the G843D mutation in the PEX1 gene. The mutation, which was identified by next-generation sequencing and confirmed by Sanger sequencing, was present in the carrier state in the parents. The patient had normal cognition and a history of Leber congenital amaurosis (LCA; see 204000).
In a patient (patient 2) with PBD1A, Majewski et al. (2011) identified compound heterozygous mutations in the PEX1 gene: G843D and a 1-bp insertion (c.2098insT; 602136.0010), resulting in a frameshift and premature termination (Ile700TyrfsTer42). The G843D mutation was identified by restriction enzyme analysis in a cohort of patients with LCA, and the c.2098insT mutation was identified by Sanger sequencing of the PEX1 gene. The patient presented with LCA at 9 months of age and had developmental delay, hypotonia, and seizures at 20 months of age.
Waterham and Ebberink (2012) noted that the G843D mutation reduces the binding between PEX1 and PEX6 (601498). The effect of the mutation is relatively mild, and cells of patients with this mutation often display peroxisomal mosaicism when cultured at 37 degrees Celsius.
Waterham and Ebberink (2012) noted that mutations in the PEX1 gene have a frequency of 58.9% among patients with Zellweger spectrum disorders. Steinberg et al. (2006) gave the allele frequency of the G843D mutation as 0.43, making it the most common mutation in PEX1-deficient patients.
In a patient with Zellweger syndrome of complementation group 1 (PBD1A; 214100), Tamura et al. (1998) identified compound heterozygosity for a 1191T-C mutation in the PEX1 gene, resulting in an leu664-to-pro (L664P) substitution, and a 171-bp deletion of nucleotide residues 1,900 to 2,070 (602136.0003). Northern blot analysis of patient and control mRNA revealed a 4.3-kb band in both, suggesting that PEX1 transcription was unaffected in the patient. Functional analysis demonstrated that cDNAs corresponding to both PEX1 mutations were defective in peroxisome-restoring activity when expressed in the patient's fibroblasts as well as in ZP107 cells.
For discussion of the 171-bp deletion of nucleotide residues 1,900 to 2,070 in the PEX1 gene that was found in compound heterozygous state in a patient with Zellweger syndrome of complementation group A (PBD1A; 214100) by Tamura et al. (1998), see 602136.0002.
In 3 patients with Zellweger syndrome (PBD1A; 214100), including a severely affected patient who was studied by Gartner et al. (1992) (patient PBD002) and another patient in whom Reuber et al. (1997) had identified a PEX1 splice donor mutation, Collins and Gould (1999) identified homozygosity or compound heterozygosity for a 1-bp insertion (c.2097insT) in exon 13 of the PEX1 gene. Screening for 2097insT in 32 additional CG1 patients revealed that 3 were homozygous and 12 heterozygous for the insertion. The authors concluded that 2097insT is a common allele in the CG1 patient population, and noted that in contrast to the other common mutation, G843D (602136.0001), which is associated with a trend toward the mild end of the ZS phenotypic spectrum, this second common PEX1 mutation is associated with severe phenotypes.
Steinberg et al. (2006) gave the allele frequency of this mutation as 0.35 in PEX1-deficient patients.
In a brother and sister with Heimler syndrome-1 (HMLR1; 234580), originally reported by Heimler et al. (1991), Ratbi et al. (2015) identified compound heterozygosity for the c.2097dupT mutation (c.2097dupT, NM_000466.2) in the PEX1 gene and a c.2114T-G transversion, resulting in a leu705-to-trp (L705W; 602136.0006) substitution. In an unrelated 24-year-old woman with HMLR1, they identified compound heterozygosity for the 2097dupT mutation and a c.1742G-C transversion, resulting in an arg581-to-pro (R581P; 602136.0007) substitution. The mutations segregated with disease in both families, and were not found in 770 in-house exomes; in addition, the L705W mutation was not found in public databases, whereas the R581P mutation was present in 1 of 121,398 alleles in the ExAC Browser (minor allele frequency less than 0.000033). The 3 affected individuals all had sensorineural hearing loss, enamel hypoplasia, and nail defects, but did not exhibit dysmorphism or additional neurologic features. Complementation assays in transfected PEX1-null cells demonstrated that the c.2097dupT variant resulted in no complementation, whereas transfection with the c.1742G-C and c.2114T-G variants rescued peroxisomal biogenesis in 23% and 58% of cells, respectively.
Among 72 mutant alleles from Australasian patients with Zellweger syndrome (ZS; 214100), neonatal adrenoleukodystrophy (NALD; see 601539), and infantile Refsum disease (see 601539), Maxwell et al. (2002) found that 7 (9.7%) had a 1-bp deletion, 2916delA, in exon 18 of the PEX1 gene, causing a frameshift mutation after gly973 and resulting in nonsense-mediated mRNA decay. The mutation resulted in complete loss of PEX1 function and was associated with a severe Zellweger syndrome phenotype. This was the third most common mutation in this cohort after the G843D (602136.0001) and exon 13 frameshift (602136.0004) mutations.
For discussion of the c.2114T-G transversion (c.2114T-G, NM_000466.2) in the PEX1 gene, resulting in a leu705-to-trp (L705W) substitution, that was found in compound heterozygous state in 2 sibs with Heimler syndrome-1 (HMLR1; 234580) by Ratbi et al. (2015), see 602136.0004.
For discussion of the c.1742G-C transversion (c.1742G-C, NM_000466.2) in the PEX1 gene, resulting in an arg581-to-pro (R581P) substitution, that was found in compound heterozygous state in 2 unrelated patients with Heimler syndrome-1 (HMLR1; 234580) by Ratbi et al. (2015), see 602136.0004 and 602136.0008.
In a 19-year-old Irish woman with sensorineural hearing loss, enamel hypoplasia, and nail defects (HMLR1; 234580), Ratbi et al. (2015) identified compound heterozygosity for a splice site mutation (c.1239+1G-T, NM_000466.2) in intron 5 of the PEX1 gene, and a c.1742G-C transversion resulting in an arg581-to-pro (R581P; 602136.0007) substitution. Ratbi et al. (2015) noted that the intron 5 splice site mutation had been identified in compound heterozygosity with a PEX1 frameshift mutation in a patient with a peroxisome biogenesis disorder in the Zellweger syndrome spectrum (see PBD1A, 214100) by Yik et al. (2009). Yik et al. (2009) reported no clinical information for the patient with the Zellweger spectrum disorder, but Ratbi et al. (2015) stated that the Irish patient did not exhibit dysmorphism or additional neurologic features. The mutations segregated with disease in the family. The previously unreported c.1742G-C mutation was not found in 770 in-house exomes but was present in 1 of 121,398 alleles in the ExAC Browser (minor allele frequency less than 0.000033). Complementation assays in PEX1-null cells demonstrated that transfection with the c.1742G-C variant rescued peroxisomal biogenesis in 23% of cells.
In a Moroccan sister and brother with sensorineural hearing loss, enamel hypoplasia, and nail defects (HMLR1; 234580), Ratbi et al. (2015) identified homozygosity for a c.3750G-A transition (c.3750G-A, NM_000466.2) in exon 23 of the PEX1 gene, resulting in a trp1250-to-ter (W1250X) substitution. The mutation segregated with disease in the family and was not found in 250 ethnically matched controls, 770 in-house exomes, or in public databases. Analysis of patient plasma, erythrocytes, and fibroblasts did not show any peroxisomal biochemical aberrations, consistent with their relatively very mild disease; however, immunofluorescence microscopy of patient fibroblasts revealed a mosaic peroxisomal pattern similar to that previously associated with hypomorphic variants. Complementation assays in PEX1-null cells demonstrated that transfection with the c.3750G-A variant rescued peroxisomal biogenesis in approximately 30% of cells.
For discussion of the 1-bp insertion (c.2098insT) in the PEX1 gene, resulting in a frameshift and premature termination (Ile700TyrfsTer42), that was found in compound heterozygous state in a patient with peroxisome biogenesis disorder-1A (PBD1A; 214100) by Majewski et al. (2011), see 602136.0001.
Collins, C. S., Gould, S. J. Identification of a common PEX1 mutation in Zellweger syndrome. Hum. Mutat. 14: 45-53, 1999. [PubMed: 10447258] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1999)14:1<45::AID-HUMU6>3.0.CO;2-J]
Crane, D. I., Maxwell, M. A., Paton, B. C. PEX1 mutations in the Zellweger spectrum of the peroxisome biogenesis disorders. Hum. Mutat. 26: 167-175, 2005. [PubMed: 16086329] [Full Text: https://doi.org/10.1002/humu.20211]
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Imamura, A., Tamura, S., Shimozawa, N., Suzuki, Y., Zhang, Z., Tsukamoto, T., Orii, T., Kondo, N., Osumi, T., Fujiki, Y. Temperature-sensitive mutation in PEX1 moderates the phenotypes of peroxisome deficiency disorders. Hum. Molec. Genet. 7: 2089-2094, 1998. [PubMed: 9817926] [Full Text: https://doi.org/10.1093/hmg/7.13.2089]
Majewski, J., Wang, Z., Lopez, I., Al Humaid, S., Ren, H., Racine, J., Bazinet, A., Mitchel, G., Braverman, N., Koenekoop, R. K. A new ocular phenotype associated with an unexpected but known systemic disorder and mutation: novel use of genomic diagnostics and exome sequencing. J. Med. Genet. 48: 593-596, 2011. [PubMed: 21862673] [Full Text: https://doi.org/10.1136/jmedgenet-2011-100288]
Maxwell, M. A., Allen, T., Solly, P. B., Svingen, T., Paton, B. C., Crane, D. I. Novel PEX1 mutations and genotype-phenotype correlations in Australasian peroxisome biogenesis disorder patients. Hum. Mutat. 20: 342-351, 2002. [PubMed: 12402331] [Full Text: https://doi.org/10.1002/humu.10128]
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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]
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