Alternative titles; symbols
HGNC Approved Gene Symbol: PEX7
SNOMEDCT: 1003862001;
Cytogenetic location: 6q23.3 Genomic coordinates (GRCh38): 6:136,822,592-136,913,934 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q23.3 | Peroxisome biogenesis disorder 9B | 614879 | Autosomal recessive | 3 |
| Rhizomelic chondrodysplasia punctata, type 1 | 215100 | Autosomal recessive | 3 |
The peroxisome biogenesis disorders (PBDs; see 214100) are a group of genetically heterogeneous autosomal recessive, lethal diseases characterized by multiple defects in peroxisome function. Braverman et al. (1997) stated that at least 11 complementation groups (CGs) had been defined by somatic cell hybridization studies in patients with PBD phenotypes. Complementation groups 1 through 10 are not predictive of phenotype and contain patients with overlapping clinical features, including Zellweger syndrome (ZS; see 214100) as the most severe phenotype, neonatal adrenoleukodystrophy (NALD; see 601539), and infantile Refsum disease (IRD; see 601539) as the least severe. Zellweger syndrome patients have developmental abnormalities as well as progressive dysfunction of the liver and central nervous system, leading to death before the end of the first year. Patients with NALD and IRD have similar but milder features. The entire collection of phenotypes was referred to by Braverman et al. (1997) as the 'Zellweger syndrome spectrum.' Metabolic abnormalities characteristic of these patients include deficiency of plasmalogens and accumulation of phytanic acid and very long chain fatty acid (VLCFA). At the cellular level, these patients exhibit deficiency of multiple peroxisomal enzymes.
The concerted action of a set of peroxisomal assembly proteins (called peroxins) encoded by PEX genes (Distel et al., 1996) is required for import of matrix proteins into peroxisomes. Matrix proteins are translated on free polyribosomes and directed to the peroxisomes by cis-acting peroxisome targeting signals (PTSs). Most use a C-terminal ser-lys-leu (SKL), or variant thereof, termed PTS1 (Subramani, 1993). A few matrix proteins utilize PTS2, an N-terminal R/KLX(5)Q/HL (Swinkels et al., 1991). In mammals, peroxisomal thiolase (604054) is the only known PTS2-targeted protein. At least 15 PEX genes were identified in yeast, and the human orthologs of 3 of these were shown to be responsible for peroxisome biogenesis disorder complementation groups: PEX2 (170993), which corresponds to complementation group 10 (CG10) and which encodes a zinc finger-containing 35-kD integral peroxisomal membrane protein (IPMP); PEX5 (600414), corresponding to CG2, which encodes the cytosolic PTS1 receptor; and PEX6 (601498), corresponding to CG4, which encodes a cytosolic AAA ATPase. Additionally, the human ortholog of PEX13, which encodes an IPMP with an SH3 domain projecting into the cytosol, was described by Gould et al. (1996), Elgersma et al. (1996), and Erdmann and Blobel (1996). The protein encoded by this gene binds the PTS1 receptor (PEX5) in a 2-hybrid assay and may function as a docking protein. Similarly, the human ortholog of PEX14 (Komori et al., 1997) has been identified and encodes another peroxisomal integral membrane protein able to bind both the PTS1 receptor and the PTS2 receptor (Albertini et al., 1997).
The yeast PEX7 gene (or PAS7), encoding the PTS2 receptor, was cloned in S. cerevisiae by Marzioch et al. (1994) and Zhang and Lazarow (1995). These investigators predicted the human ortholog to be the site of the mutation causing classic rhizomelic chondrodysplasia punctata (RCDP1; 215100) which is the peroxisome biogenesis disorder that belongs to CG11. In yeast, the PEX7 protein is a member of the WD40 family of proteins and interacts directly with the PTS2 sequence of peroxisomal thiolase or PTS2 reporter proteins. Mutant pex7 yeast has morphologically normal peroxisomes and normal PTS1 import but fails to import PTS2-targeted proteins (Marzioch et al., 1994; Zhang and Lazarow, 1995). Fibroblasts from RCDP type 1 patients have a peroxisomal import defect virtually identical to that of pex7 mutant yeast (Motley et al., 1994).
Peroxisomal biogenesis disorder CG11 (the second most numerous complementation group) includes patients with classic rhizomelic chondrodysplasia punctata. Compared to patients in the Zellweger syndrome spectrum, RCDP patients have a higher level of phytanic acid and a more profound deficiency of plasmalogens but normal levels of VLCFA. To identify the molecular defect of RCDP, Braverman et al. (1997) used a 'homology probing' strategy to probe the EST database; with the yeast PEX7 protein sequence they could identify candidate cDNAs for the human and murine PEX7 genes. They cloned a human homolog encoding a 323-amino acid protein and a mouse homolog encoding a 318-amino acid protein. The human polypeptide shares 91% and 33% amino acid identity with its murine and S. cerevisiae orthologs, respectively. Braverman et al. (1997) showed that expression of full-length human and murine PEX7 cDNAs restored PTS2-mediated import to RCDP fibroblasts and they identified functionally significant mutations in the PEX7 genes of RCDP patients, 1 of which (leu292 to ter; 601757.0001) accounts for about half of all RCDP mutant genes. As expected for a gene involved in the biogenesis of a ubiquitous organelle, they detected a 1.7-kb human PEX7 transcript in all tissues examined. In tissues with highest PEX7 expression (pancreas, skeletal muscle, and heart), a second transcript of approximately 1.5 kb was present in low abundance. The significance of this shorter transcript is unclear. Motley et al. (1997) cloned PEX7 based on its similarity to its yeast ortholog and stated that all RCDP patients in CG11 were found to contain mutations in PEX7. A PEX7 mutation (leu292 to ter) cosegregated with the disease, and expression of PEX7 in RCDP fibroblasts from CG11 corrected the PTS2 protein import deficiency. Purdue et al. (1997) likewise cloned the human ortholog of yeast PEX7 and demonstrated that the gene is defective in RCDP.
Braverman et al. (2000) demonstrated that the transcribed portion of the PEX7 gene is 102 kb and contains 10 exons varying from 57 to 482 bp.
Braverman et al. (1997) mapped the PEX7 gene to 6q22-q24 by probing a rodent/human hybrid mapping panel with a cDNA probe followed by regionalization with a radiation hybrid panel.
Gross (2014) mapped the PEX7 gene to chromosome 6q23.3 based on an alignment of the PEX7 sequence (GenBank BC006268) with the genomic sequence (GRCh37).
Rhizomelic Chondrodysplasia Punctata Type 1
Motley et al. (2002) reported the mutational spectrum in the PEX7 gene of 78 patients (including 5 pairs of sibs) clinically and biochemically diagnosed with RCDP type 1 (RCDP1; 215100). They found 22 different mutations, including 18 novel ones. Furthermore, they showed by functional analysis that disease severity correlated with PEX7 allele activity: expression of 8 different alleles from patients with severe RCDP failed to restore the targeting defect in RCDP fibroblasts, whereas 2 alleles found only in patients with mild disease complemented the targeting defect upon overexpression. Surprisingly, one of the mild alleles comprises a duplication of nucleotides 45-52 (601757.0005), which was predicted to lead to a frameshift at codon 17 and an absence of functional peroxin-7. The ability of this allele to complement the targeting defect in RCDP cells suggested that frame restoration occurs, resulting in full-length functional peroxin-7, which leads to amelioration of the predicted severe phenotype. This was confirmed in vitro by expression of the 8-nucleotide duplication-containing sequence fused in different reading frames to the coding sequence of firefly luciferase in COS cells.
Braverman et al. (2002) analyzed 60 probands with RCDP and identified 24 PEX7 alleles, accounting for 95% of the mutant PEX7 genes in their sample. Of these, 50% were L292X (601757.0001), 13% were IVS9+1G-C (601757.0006), and the remainder were mostly private mutations. IVS9+1G-C occurred on at least 3 different haplotypes and thus appeared to result from recurrent mutation.
Peroxisome Biogenesis Disorder 9B
A clinical phenotype indistinguishable from that of classic Refsum disease (266500), caused by mutation in the PHYH gene (602026), can be caused by mutation in the PEX7 gene; see PBD9B (614879) for a complete phenotypic description.
Braverman et al. (2002) and van den Brink et al. (2003) demonstrated mutations in the PEX7 gene (see, e.g., 601757.0007-601757.0011) in patients diagnosed with Refsum disease, an autosomal recessive disorder characterized by progressive adult retinitis pigmentosa, peripheral neuropathy, anosmia, and cerebellar ataxia, among other features. The onset of clinical symptoms in adolescence is due to gradual accumulation of phytanic acid. The peroxisomal enzyme phytanoyl-CoA hydroxylase (PHYH) catalyzes the first step of alpha-oxidation of phytanic acid. Biochemical analyses in Refsum patients reported by van den Brink et al. (2003) showed defects not only in phytanic acid alpha-oxidation, but also in plasmalogen synthesis and peroxisomal thiolase. These findings indicated that mutations in PEX7 may result in a broad clinical spectrum ranging from severe rhizomelic chondrodysplasia punctata to relatively mild Refsum disease, and that clinical diagnosis of conditions involving retinitis pigmentosa, ataxia, and polyneuropathy may require a full screen of peroxisomal functions.
Jansen et al. (2004) reviewed 5 sequence variants in the PEX7 gene causing a Refsum disease phenotype.
Braverman et al. (2002) found the phenotypic spectrum of RCDP to be broader than previously recognized, as it includes minimally affected individuals at the mild end of the spectrum. To relate PEX7 genotype and phenotype, they evaluated the consequence of the disease mutation on PEX7 RNA by Northern analysis and RT-PCR. They evaluated the function of the encoded PEX7 protein by expressing selected alleles in fibroblasts from RCDP patients and assaying their ability to restore import of a PTS2 marker protein. Residual activity of the mutant protein and reduced amounts of normal PEX7 protein were associated with milder and variant phenotypes.
Brites et al. (2003) generated Pex7-knockout mice (Pex7 -/-), which were severely hypotonic at birth and exhibited growth impairment. Mortality was highest in the perinatal period, although some Pex7 -/- mice survived beyond 18 months. Biochemically, Pex7 -/- mice displayed a severe depletion of plasmalogens, impaired alpha-oxidation of phytanic acid, and impaired beta-oxidation of very long chain fatty acids. Pex7 -/- mice displayed increased neuronal density in parts of the cerebral cortex and had a delay in neuronal migration. Analysis of bone ossification in newborn Pex7 -/- mice revealed a defect in ossification of distal bone elements of the limbs as well as parts of the skull and vertebrae.
In 26 of 36 probands with rhizomelic chondrodysplasia punctata (RCDP1; 215100), Braverman et al. (1997) found a nonsense mutation, leu292 to ter (L292X). All these probands had a severe phenotype. The same mutation, resulting from an A-to-T transversion at nucleotide 875, was identified by Purdue et al. (1997) and Motley et al. (1997). Braverman et al. (1997) suggested that founder effect may account for the high frequency of L292X in northern Europeans; none of the 26 patients either heterozygous or homozygous for L292X were of African or Asian descent.
In a Chilean boy with a typical RCDP phenotype and an inversion of chromosome 8 reported by Castillo-Taucher et al. (1991), Shimozawa et al. (1999) found the L292X mutation in compound heterozygous state with A218V (601757.0002). The inversion was also present in the child's unaffected mother.
Motley et al. (2002) found the L292X mutation to be by far the most common mutation causing RCDP type 1, followed by the A218V missense mutation (601757.0002). In their large series, these 2 mutations were approximately 52% and 12%, respectively, which is similar to the frequencies of 49% and 6% reported by Braverman et al. (2000), who analyzed 36 patients with RCDP type 1.
Braverman et al. (1997) found an ala218-to-val (A218V) amino acid substitution in PEX7 in 3 probands with rhizomelic chondrodysplasia punctata (RCDP1; 215100), including 2 with a milder phenotype (PBD9B; 614879) than that in probands with the L292X mutation (601757.0001). The substitution resulted from a 653C-T transition. Motley et al. (1997) also detected this mutation in RCDP patients.
In 5 probands with rhizomelic chondrodysplasia punctata (RCDP1; 215100), Braverman et al. (1997) found a gly217-to-arg (G217R) mutation resulting from a 649G-A transition in exon 7 of the PEX7 gene in compound heterozygosity with L292X (601757.0001). They also found 1 patient who was homozygous for the G217R mutation.
In a 7-year-old girl, the first Japanese individual to be diagnosed biochemically with rhizomelic chondrodysplasia punctata (RCDP1; 215100), Shimozawa et al. (1999) identified an arg232-to-ter (R232X) mutation in the PEX7 gene, which had been inherited from her consanguineous parents. This patient was previously reported by Suzuki et al. (1993) and had severe psychomotor retardation. The nonsense mutation deleted all of the last 2 WD40 repeats in the PEX7 gene and was sufficient to inactivate functions of the PEX7 gene.
In 2 patients with a mild chondrodysplasia punctata phenotype with no rhizomelia (PBD9B; 614879), one from a Swiss family and the other from a French, Motley et al. (2002) detected homozygosity for an 8-nucleotide duplication of nucleotides 45-52 in the PEX7 cDNA (52dupGGGACGCC), predicted to result in frameshift at codon 17 in exon 1 of the PEX7 gene. Coexpression of the 8-bp dup allele with PTS2-tagged GFP in skin fibroblasts from a patient homozygous for a PEX7 null mutation resulted in partial restoration of PTS2-mediated peroxisomal protein import. Although the mutation was predicted to lead to absence of functional peroxin-7, the in vitro results suggested that frame restoration occurs.
In a study of 60 probands with rhizomelic chondrodysplasia punctata (RCDP1; 215100), Braverman et al. (2002) found 16 cases of the IVS9+1G-C splice site mutation, which occurred on at least 3 different haplotypes and thus appeared to result from recurrent mutation.
In a 58-year-old patient with a mild peroxisome biogenesis disorder (PBD9B; 614879), Braverman et al. (2002) found compound heterozygosity for 2 truncating mutations in the PEX7 gene: tyr115 to ter and IVS3-10A-G (601757.0008). This patient had been diagnosed with Refsum disease (266500) by Sigvald Refsum in 1948 (Horn et al., 2007). As mutations in the peroxisomal enzyme PAHX (602026) result in classic Refsum disease, Braverman et al. (2002) hypothesized that mutations in the other peroxisomal enzyme, PEX7, result in the accumulation of phytanic acid over time to produce the Refsum disease-like phenotype.
For discussion of the splice site mutation in the PEX7 gene (IVS3-10A-G) that was found in compound heterozygous state in a patient with a mild peroxisome biogenesis disorder (PBD9B; 614879) by Braverman et al. (2002), see 601757.0007.
In 2 probands with a mild peroxisome biogenesis disorder (PBD9B; 614879), van den Brink et al. (2003) found compound heterozygosity for a 120C-G transversion in the PEX7 gene, resulting in a tyr40-to-ter (Y40X) mutation. Both probands had received a clinical diagnosis of Refsum disease (266500). The Y40X mutation had previously been observed in patients with classic rhizomelic chondrodysplasia punctata type 1 (RCDP1; 215100) with a severe clinical presentation (Motley et al., 2002). The comparatively mild phenotype in the 2 probands reported by van den Brink et al. (2003) seemed attributable to the presence of a second mutation associated with residual activity of the gene product. This was a 7-bp duplication of nucleotides 12-18, predicted to cause a frameshift leading to a premature termination codon at amino acid position 57 (601757.0010) in the first patient, and a thr14-to-pro amino acid substitution (T14P; 601757.0011) in the other. In the first family, clinical features included onset in the first and second decades of retinitis pigmentosa, anosmia, short fifth metacarpal and palmar ichthyosis, pes cavus, musculature weakness, and nerve hypertrophy. One patient was mildly affected. The proband of the second family was born with bilateral cataracts, but presented to a neurology clinic at age 20 years with polyneuritis and onset of ataxia at age 19 years. She had bilateral short fifth metacarpals and metatarsals, and mild retinitis pigmentosa. Her brother presented at age 34 years with mild ataxia and mild retinitis pigmentosa but no night blindness, obvious anosmia, or deafness. Neither patient had any episodes of ichthyosis or signs of deafness. One other male sib died of supposed poliomyelitis with symptoms of weakness and ataxia at age 12 years.
For discussion of the 7-bp duplication in the PEX7 gene that was found in compound heterozygous state in a patient with a mild peroxisome biogenesis disorder (PBD9B; 614879) by van den Brink et al. (2003), see 601757.0009.
For discussion of the thr14-to-pro (T14P) mutation in the PEX7 gene that was found in compound heterozygous state in a patient with a mild peroxisome biogenesis disorder (PBD9B; 614879) by van den Brink et al. (2003), see 601757.0009.
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