HGNC Approved Gene Symbol: PPOX
SNOMEDCT: 58275005;
Cytogenetic location: 1q23.3 Genomic coordinates (GRCh38) : 1:161,165,728-161,178,013 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q23.3 | Variegate porphyria | 176200 | Autosomal dominant | 3 |
| Variegate porphyria, childhood-onset | 620483 | Autosomal recessive | 3 |
Protoporphyrinogen oxidase (EC 1.3.3.4), the penultimate enzyme in the heme biosynthetic pathway, catalyzes the 6-electron oxidation of protoporphyrinogen IX to form protoporphyrin IX. The enzyme is located in the inner membrane of mitochondria from various tissues, including liver, lymphocytes, and cultured fibroblasts (summary by Nishimura et al., 1995).
Nishimura et al. (1995) cloned and characterized human PPOX cDNA and found that it consists of 477 amino acids with a molecular mass of 51 kD. The PPOX protein shows sequence similarity to the hemY gene of Bacillus subtilis. The N-terminal portion contains a conserved region that forms the dinucleotide-binding site seen in many flavin-containing proteins. Northern blot analysis detected a 1.8-kb mRNA in human K562 and HepG2 cells. When expressed in COS-1 monkey cells, the human PPOX cDNA produced much higher levels of PPOX activity, which was inhibited by acifluorfen, a specific inhibitor of PPOX. The human protein could also be detected in the mitochondria of the transfected cells despite the fact that the protein lacks the apparent transport-specific leader sequence seen in a number of other mitochondrial proteins.
Taketani et al. (1995) demonstrated that the PPOX gene has 13 exons and spans about 8 kb. The exon/intron boundary sequences conformed to the consensus sequence. Primer extension analysis revealed 2 major transcriptional initiation sites in a region with sequence motifs characteristic of the promoter. The promoter region contains multiple Sp1 elements, CCAAT boxes, and potential GAT-1 binding sites. Mapping of the 5-prime end of PPOX mRNA by PCR indicated that the same transcripts exist in erythroid and nonerythroid cells. Puy et al. (1996) confirmed the intron/exon structure of PPOX and reported its complete genomic DNA sequence.
Taketani et al. (1995) showed by Southern blotting of human genomic DNA that there is a single copy of the PPOX gene, and by fluorescence in situ hybridization (FISH) they mapped the gene to 1q22. This represented a puzzling discrepancy with the mapping of VP to chromosome 14 by linkage. Taketani et al. (1995) suggested that the product of a gene on chromosome 14 may interact with PPOX protein to maintain normal enzyme activity or to affect expression of the PPOX gene.
Roberts et al. (1995) mapped the PPOX gene to 1q23 by FISH; furthermore, they showed that variegate porphyria is linked to DNA markers in the 1q21-q25 region. They concluded that the findings spoke against locus heterogeneity in VP.
Variegate Porphyria
Deybach et al. (1996), Meissner et al. (1996), Warnich et al. (1996), and Lam et al. (1997) identified heterozygous mutations in the PPOX gene (see, e.g., 600923.0001-600923.0005) in patients with variegate porphyria (VP; 176200).
In 2 unrelated women with variegate porphyria, Frank et al. (1998) identified heterozygosity for the same missense mutation (R168H; 600923.0006). Segregation analysis revealed that an unaffected son of one of the probands also carried the R168H variant, which was not found in controls.
Wiman et al. (2003) stated that approximately 80 individuals from 28 apparently unrelated families had been diagnosed with VP in Sweden. Genetic analysis of the PPOX gene in 17 of these families identified 10 different mutations, only 1 of which had previously been reported. Mutation analysis in family members revealed 2 adults and 4 children who were silent carriers of the VP trait.
Borrero Corte et al. (2019) sequenced the PPOX gene in 8 unrelated Spanish patients with variegate porphyria, 4 of whom had only cutaneous photosensitivity, 3 of whom experienced only acute symptoms, and 1 of whom had both. The authors identified heterozygosity for known VP-associated mutations in all patients (see, e.g., 600923.0006). No genotype/phenotype correlations were observed.
Childhood-Onset Variegate Porphyria
In an Afrikaner girl with photosensitivity, severe brachydactyly, seizures, developmental delay, sensory neuropathy, and an abnormal porphyrin excretion pattern (VPCO; 620483), Meissner et al. (1996) identified compound heterozygosity for missense mutations in the PPOX gene: an R59W substitution (600923.0003) and an R168C substitution (600923.0004). Her mother, who met the criteria for VP, was heterozygous for the R59W mutation, and her father, who had normal porphyrin biochemistry and a 25% reduction in PPO activity, was heterozygous for the R168C variant. The authors also detected the R59W mutation in 43 of 45 patients with autosomal dominant VP (176200) from 26 of 27 South African families; genealogic analysis of 1 of the South African families demonstrated relatedness to the original South African VP family tree, suggesting a founder effect. Functional analysis of the R59W mutation demonstrated that the mutant enzyme had an almost undetectable catalytic rate but a relatively invariant K(m), consistent with the 50% reduction in PPO activity seen in the proband's mother.
In a 20-year-old woman with apparent autosomal recessive variegate porphyria, who in addition to cutaneous manifestations exhibited impaired intellectual development and hand deformities, Frank et al. (1998) identified compound heterozygosity for missense mutations in the PPOX gene: a G169E substitution (600923.0014) and a G358R substitution (600923.0015). Her asymptomatic parents, who both exhibited approximately half-normal levels of PPO activity, were each heterozygous for 1 of the mutations, neither of which was found in 50 unrelated controls.
Roberts et al. (1998) confirmed the molecular characterization of the rare 'homozygous' variant of variegate porphyria. They identified PPOX mutations on both alleles of 5 of the 11 unrelated patients with apparent autosomal recessive VP reported to that time. Two patients were homozygous for missense mutations (D349A, 600923.0007 and A433P), whereas 2 were compound heterozygous for a G358R substitution and either a G169E substitution or a splice site mutation, respectively, and the remaining patient was compound heterozygous for a 12-bp insertion and another splice site mutation. Functional analysis by prokaryotic expression showed that the D349A and A433P mutations and 1 missense mutation in each of the 3 heteroallelic patients (G538R in 2 patients and 657ins12) preserved some PPOX activity (9.5-25% of wildtype). Mutations on the other allele of the heteroallelic patients abolished or markedly decreased activity. There was no relation between genotype assessed by functional analysis and the presence or severity of noncutaneous manifestations. All the mutations found in the homozygous patients were absent from 104 unrelated patients with autosomal dominant VP. The authors concluded that mild PPOX mutations occur in the general population but have a very low or no clinical penetrance in heterozygotes.
In a 36-year-old British woman with severe cutaneous manifestations of variegate porphyria and brachydactyly, Palmer et al. (2001) identified compound heterozygosity for mutations in the PPOX gene: an in-frame 12-bp insertion (600923.0010) and a splice site mutation (600923.0011). The proband's mother, who was heterozygous for the splice site mutation, experienced 3 neuroabdominal episodes, 2 of which followed drug ingestion; she had no cutaneous manifestations. A maternal first cousin, who also carried the splice site mutation, was asymptomatic. DNA was unavailable from the proband's deceased father, who was reported to be asymptomatic.
In a Finnish boy with apparent homozygous variegate porphyria, Kauppinen et al. (2001) identified compound heterozygosity for 2 missense mutations in the PPOX gene: an I12T substitution (600923.0012) and a P256R substitution (600923.0013). Affected members of another Finnish family were compound heterozygous for the same mutations, suggesting a common ancestor. One heterozygous carrier in each family was mildly symptomatic.
In a 33-year-old Chinese man with childhood-onset variegate porphyria, Cho et al. (2021) sequenced the PPOX gene and identified homozygosity for a missense mutation (V270L; 600923.0018) at the first base of exon 8 of the PPOX gene. His unaffected consanguineous parents were heterozygous for the mutation. Functional analysis revealed that the mutation affected splicing, resulting in exon skipping that was predicted to result in a truncated protein.
In a patient (P1) of French Caucasian origin with variegate porphyria (VP; 176200), Deybach et al. (1996) identified heterozygosity for a 1-bp insertion (c.1022insG) in exon 7 of the PPOX gene, producing a frameshift that resulted in a premature stop codon.
In 3 patients (P2-P4) from 2 unrelated French Caucasian families with variegate porphyria (VP; 176200), Deybach et al. (1996) found heterozygosity for a G-to-C transversion at nucleotide 971 (c.971G-C), resulting in a gly232-to-arg (G232R) substitution. In 1 of the families, consisting of 14 members over 3 generations, the authors demonstrated that the mutation segregated fully with deficient PPOX activity.
In a girl of Afrikaner origin with photosensitivity, severe brachydactyly, seizures, developmental delay, sensory neuropathy, and an abnormal porphyrin excretion pattern (VPCO; 620483), who was originally described by Hift et al. (1993), Meissner et al. (1996) identified compound heterozygosity for missense mutations in the PPOX gene: a C-to-T transition in exon 3, resulting in an arg59-to-trp (R59W) substitution within the predicted FAD (see 610595) dinucleotide-binding motif, and a C-to-T transition in codon 168, resulting in an arg168-to-cys (R168C; 600923.0004) substitution. The proband's mother, who met the criteria for autosomal dominant VP (176200), was heterozygous for the R59W mutation, and her father, who had normal porphyrin biochemistry and a 25% reduction in PPO activity, was heterozygous for the R168C variant. The authors also detected the R59W substitution in 43 of 45 patients with VP from 26 of 27 South African families, but not in 34 unaffected relatives or 9 unrelated British patients with PPO deficiency. Genealogic analysis of 1 of the South African families demonstrated relatedness to the original South African VP family tree (Dean, 1972), suggesting a founder effect. Functional analysis of the R59W mutation demonstrated that the mutant enzyme had an almost undetectable catalytic rate but a relatively invariant K(m), consistent with the reduced PPO activity seen in the VP patients.
Warnich et al. (1996) identified heterozygosity for the R59W mutation (c.452C-T) in 15 of 17 South African patients with variegate porphyria. This mutation was shown to create a StyI restriction site in the gene. It was also shown to be associated with C(26)-C(150), 1 of 4 potential haplotypes defined by 2 polymorphisms in exon 1 of the PPOX gene.
De Villiers et al. (1999) identified a patient with severe variegate porphyria carrying the R59W allele of the PPOX gene who was also compound heterozygous for mutations in the HFE gene (Q127H, 235200.0007 and H63D, 235200.0002). The authors also found that the mutant allele frequency of the HFE C282Y mutation (235200.0001) was significantly lower in 73 apparently unrelated VP patients carrying the R59W mutation than in 102 controls drawn from the same population in South Africa (p = 0.005). The authors concluded that their findings supported data on the involvement of the HFE gene in the porphyria phenotype.
In a 7-year-old girl of Afrikaner origin (family 1) with severe cutaneous photosensitivity, brachydactyly, and sensory neuropathy, Corrigall et al. (2000) identified compound heterozygosity for the recurrent R59W mutation in the PPOX gene, and an A-to-G transition in exon 10, resulting in a tyr348-to-cys (Y348C; 600923.0016) substitution. Testing of 10 additional family members revealed heterozygosity for the R59W mutation in the proband's asymptomatic mother and 12-year-old sister; the mother showed a fecal porphyrin excretion pattern typical of VP, but the sister was biochemically negative. The proband's asymptomatic father, half brother, and half sister were heterozygous for the Y348C mutation; her father had a normal fecal porphyrin excretion profile but showed a small peak at 625 nm on plasma fluoroscanning, her half brother had a typical VP fecal porphyrin excretion pattern but normal plasma fluoroscan, and her half sister was biochemically negative. The Y348C mutation was shown to have arisen de novo in the father. In 2 South African sisters of mixed-race origin (family 2), 1 of whom experienced acute porphyric attacks and severe cutaneous photosensitivity and the other of whom showed typical VP skin disease, Corrigall et al. (2000) identified compound heterozygosity for R59W in PPOX and a R138P mutation (600923.0017). None of the mutations was found in 50 ethnically matched controls. Noting that the sisters who were compound heterozygous for the R59W and R138P mutations did not manifest symptoms in early childhood, the authors suggested that the R138P mutation might have more residual PPO activity than the Y438C mutation.
For discussion of the C-to-T transition in codon 168 of the PPOX gene, resulting in an arg168-to-cys (R168C) substitution, that was found in compound heterozygous state in a girl of Afrikaner origin with childhood-onset variegate porphyria (VPCO; 620483) by Meissner et al. (1996), see 600923.0003.
Warnich et al. (1996) identified heterozygosity for this exon 6 mutation (R168C) in the PPOX gene in 1 of 17 South African patients with variegate porphyria (VP; 176200). This mutation would abolish a DsaI restriction site in genomic DNA of affected individuals, and was shown to be associated with a different haplotype for the exon 1 polymorphism A(26)-C(150) than were the R59W (600923.0003) or H20P (600923.0005) mutations.
In 1 of 17 unrelated patients with variegate porphyria (VP; 176200) from South Africa, Warnich et al. (1996) identified heterozygosity for a c.336A-C transversion in exon 2 of the PPOX gene that resulted in a his20-to-pro (H20P) amino acid substitution. The mutation was associated with the same exon 1 polymorphism haplotype as the R59W mutation (600923.0003).
In a 57-year-old woman (proband 1) and an unrelated 38-year-old woman (proband 2) with variegate porphyria (VP; 176200), Frank et al. (1998) identified a c.502G-A transition in exon 6 of the PPOX gene, resulting in an arg168-to-his (R168H) substitution at a highly conserved residue. The mutation occurred in the same codon as the previously reported arg168-to-cys mutation (R168C; 600923.0004) and, noting that the mutation involved a putatively hypermutable CpG dinucleotide, the authors suggested that R168 might be a mutational hotspot. Segregation analysis in the family of proband 1 revealed that her unaffected son also carried the R168H variant, indicating incomplete penetrance; relatives of proband 2 were unavailable for study. The mutation was not found in 50 unrelated controls.
Frank et al. (2001) found the same R168H mutation on separate haplotypes in 6 VP patients from 3 unrelated families in Chile. The authors suggested that R168H is a hotspot mutation.
In 2 unrelated Spanish women with VP, including an 18-year-old (patient 2) with only cutaneous photosensitivity and a 64-year-old (patient 3) with only acute symptoms, Borrero Corte et al. (2019) identified heterozygosity for the previously reported R168H mutation in the PPOX gene.
In a boy (patient 3) with childhood-onset variegate porphyria (VPCO; 620483), Roberts et al. (1998) found homozygosity for a c.1046A-C transversion in exon 10 of the PPOX gene, resulting in an asp349-to-ala (D349A) substitution. The patient, a 16-year-old male at the time of study, was the offspring of consanguineous Lebanese parents and had developed severe skin lesions from the age of 8 months. The diagnosis of homozygous VP was made at the age of 7 years. The patient had no mental retardation, convulsions, nystagmus, or growth retardation.
In a 31-year-old South African woman of mixed racial ancestry with variegate porphyria (VP; 176200), Corrigall et al. (1998) identified a heterozygous 2-bp deletion in exon 6, c.537delAT, which resulted in a premature stop codon 11 codons downstream. The mutation was also found in her affected cousin. Among 31 family members tested, 17 were found to carry the mutation; 13 of these 17 showed biochemical evidence of VP in urine and stool porphyrin analysis, whereas the other 4 had normal porphyrin excretion patterns. Only 3 of the 17 were symptomatic. This rare variant was the first reported deletion in the PPOX gene in a South African family. Corrigall et al. (1998) noted that the great majority of South African patients with VP carry the R59W mutation of the PPOX gene (600923.0003). H20P (600923.0005) and R168C (600923.0004) are uncommon mutations in South African families.
Frank et al. (2001) found an apparent founder mutation, c.1239delTACAC, on the same chromosome 1 haplotype in 11 mutation carriers from 4 Chilean families with variegate porphyria (VP; 176200).
In a 36-year-old British woman with severe cutaneous manifestations of variegate porphyria and brachydactyly (VPCO; 620483), Palmer et al. (2001) identified compound heterozygosity for mutations in the PPOX gene: an in-frame 12-bp insertion (c.657-658insAAGGCCAGCGCC), encoding 4 additional amino acid residues (KASA), and a splice site mutation at the donor site of exon 11 (IVS11-1G-A; 600923.0011). The proband's mother, who was heterozygous for the splice site mutation, experienced 3 neuroabdominal episodes, 2 of which followed drug ingestion (VP; 176200); she had no cutaneous manifestations. A maternal first cousin, who also carried the splice site mutation, was asymptomatic. DNA was unavailable from the proband's deceased father, who was reported to be asymptomatic. The patient had onset of skin fragility, scarring, and blisters on sun-exposed sites at 9 months of age. She experienced a febrile convulsion at 4 years of age, had delayed bone age at 19 years of age, and was of short stature.
For a discussion of the IVS11-1G-A mutation in the PPOX gene that was found in compound heterozygous state in a woman with childhood-onset variegate porphyria (VPCO; 620483) by Palmer et al. (2001), see 600923.0010. The mutation had been transmitted by her mother, who had experienced 3 neuroabdominal porphyric episodes, 2 of which followed drug ingestion (VP; 176200); she had no cutaneous manifestations.
In a Finnish boy with childhood-onset variegate porphyria (VPCO; 620483), originally described by Mustajoki et al. (1987), Kauppinen et al. (2001) identified compound heterozygosity for mutations in the PPOX gene: a c.35T-C transition in exon 2 of the PPOX gene, resulting in an ile12-to-thr (I12T) substitution, and a c.767C-G transversion in exon 7, resulting in a pro256-to-arg (P256R; 600923.0013) substitution. His asymptomatic first-cousin parents and his grandmothers were heterozygous for the mutations. Mustajoki et al. (1987) reported that 1 of the grandmothers was mildly affected, experiencing blistering on exposed skin in the summer with residual scarring. Affected members of another Finnish family were compound heterozygous for the same mutations, suggesting a common ancestor. Kauppinen et al. (2001) noted that 1 heterozygous carrier of the I12T mutation in the second Finnish family had experienced 2 acute attacks in her youth associated with sulfonamides. Expression of the mutant enzymes in E. coli and COS-1 cells showed that the I12T mutation resulted in loss of enzyme function, whereas the P256R mutation resulted in less than half of normal PPOX activity in the prokaryotic system and almost normal activity in the eukaryotic cells. Kauppinen et al. (2001) noted that the P256R change had been identified as a polymorphism in western European populations (Whatley et al., 1999).
For discussion of the c.767C-G transition in exon 7 of the PPOX gene, resulting in a pro256-to-arg (P256R) substitution, that was found in compound heterozygous state in affected members of 2 Finnish families with childhood-onset variegate porphyria (VPCO; 620483) by Kauppinen et al. (2001), see 600923.0012.
In a 20-year-old woman with childhood-onset variegate porphyria (VPCO; 620483), originally described by Norris et al. (1990), who in addition to cutaneous manifestations exhibited impaired intellectual development and hand deformities, Frank et al. (1998) identified compound heterozygosity for missense mutations in the PPOX gene: a c.505G-A transition in exon 6, resulting in a gly169-to-glu (G169E) substitution at a highly conserved residue, and a c.1071G-A transition in exon 10, resulting in a gly358-to-arg (G358R; 600923.0015) substitution at a conserved residue. Her asymptomatic parents were each heterozygous for 1 of the mutations, neither of which was found in 50 unrelated controls. Frank et al. (1998) noted that the patient had PPO activity that was less than 20% of normal, whereas both parents had approximately half-normal levels of PPO activity.
For discussion of the c.1071G-A transition in exon 10 of the PPOX gene, resulting in a gly358-to-arg (G358R) substitution, that was found in compound heterozygous state in a 20-year-old woman with childhood-onset variegate porphyria (VPCO; 620483) by Frank et al. (1998), see 600923.0014.
For discussion of the A-to-G transition in exon 10 of the PPOX gene, resulting in a tyr348-to-cys (Y348C) substitution, that was found in compound heterozygous state in a 7-year-old girl of Afrikaner origin (family 1) with childhood-onset variegate porphyria (VPCO; 620483) by Corrigall et al. (2000), see 600923.0003.
For discussion of the G-to-C transversion in exon 5 of the PPOX gene, resulting in an arg138-to-pro (R138P) substitution, that was found in compound heterozygous state in 2 South African sisters of mixed-race origin (family 2) with childhood-onset variegate porphyria (VPCO; 620483) by Corrigall et al. (2000), see 600923.0003.
In a 33-year-old Chinese man with childhood-onset variegate porphyria (VRCO; 620483), Cho et al. (2021) identified homozygosity for a c.808G-T transversion (c.808G-T, NM_000309.3) at the first base of exon 8 in the PPOX gene, resulting in a val270-to-leu (V270L) substitution. His unaffected consanguineous parents were heterozygous for the mutation, which was not found in the gnomAD v.2.1.1 database. Functional analysis in transfected HEK293 cells revealed only a 200-bp band similar to the vector-only control, with absence of the normal 300-bp product, suggesting aberrant splicing. Sanger sequencing confirmed skipping of exon 8, causing a frameshift predicted to result in a premature termination codon (Val270CysfsTer17).
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