Alternative titles; symbols
HGNC Approved Gene Symbol: CPOX
SNOMEDCT: 190915002, 238056003;
Cytogenetic location: 3q11.2 Genomic coordinates (GRCh38) : 3:98,570,488-98,593,611 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q11.2 | Coproporphyria | 121300 | Autosomal dominant; Autosomal recessive | 3 |
| Harderoporphyria | 618892 | Autosomal recessive | 3 |
The CPOX gene encodes coproporphyrinogen oxidase (EC 1.3.3.3), the sixth enzyme of the heme biosynthetic pathway. This soluble protein localizes to the mitochondria and catalyzes the 2-step oxidative decarboxylation of the heme precursor coproporphyrinogen III to protoporphyrinogen IX via the tricarboxylic intermediate harderoporphyrinogen (summary by Hasanoglu et al., 2011).
Kohno et al. (1993) purified CPO to apparent homogeneity from bovine liver, determined partial amino acid sequences, and used degenerate oligonucleotides based on the sequences of trypsin-digested peptides to amplify in a polymerase chain reaction a fragment of CPO DNA, using bovine kidney cell cDNA as a starting template. This fragment was used as a hybridization probe to isolate full-length CPO clones from a mouse erythroleukemia cell cDNA library. Sequence analysis demonstrated that CPO comprises 354 amino acid residues with a putative leader sequence of 31 amino acid residues, the mature protein having 323 amino acid residues. Martasek et al. (1994) determined the sequence of the human cDNA and reported the predicted amino acid sequence.
Delfau-Larue et al. (1994) reported the exon/intron organization of the entire CPO gene, including sequences of all exon/intron boundaries and its 5-prime and 3-prime flanking regions. The gene spans about 14 kb and consists of 7 exons and 6 introns. Introns vary in size from 269 bp to 5 kb and all have consensus sequences at their boundaries. The promoter region is GC-rich and contains multiple potential Sp1 elements, CACCC boxes, and potential GATA-1 binding sites.
Using fluorescence in situ hybridization, Cacheux et al. (1994) mapped the CPO gene to chromosome 3q12 and confirmed the localization by cosegregation of the human gene with chromosome 3 in a panel of human/rodent somatic hybrids.
Coproporphyria
In a patient previously reported by Grandchamp et al. (1977) and thought to have homozygous coproporphyria (HCP; 121300), Martasek et al. (1994) identified heterozygosity for an arg231-to-trp mutation in the CPO gene (612732.0001).
Rosipal et al. (1999) studied CPO DNA from 7 unrelated heterozygous HCP patients from France, Holland, and the Czech Republic. Seven novel mutations and 2 new polymorphisms were detected. Among these mutations, 2 were missense, 2 were nonsense mutations, 2 were small deletions, and 1 was a splicing mutation. The 2 polymorphisms were located in the noncoding part of the gene. Rosipal et al. (1999) stated that a total of 19 different CPO gene defects had been reported.
Lamoril et al. (2001) studied 17 unrelated British patients with HCP. They identified 10 novel and 4 previously reported CPO mutations in 15 of the 17 patients. All but 1 mutation were restricted to a single family, with a predominance of missense mutations. Both patients in whom mutations were not identified had an unequivocal diagnosis of HCP. Complete deletions of the CPO gene were excluded by showing that both patients were heterozygous for at least 1 intragenic SNP. It is probable that the causative mutations either lie outside the regions that were sequenced or were partial deletions or insertions not detected by the PCR-based methods. The findings of this study suggested that single copies of CPO mutations that are known or predicted to cause 'homozygous' HCP or harderoporphyria can produce typical HCP in adults and demonstrated that the severity of the phenotype does not correlate with the degree of inactivation by mutation of the coproporphyrinogen oxidase enzyme.
In 5 of 9 Swedish families with HCP, Wiman et al. (2002) identified mutations in the CPO gene. In each of 2 of the families, a novel mutation was identified: ser208 to phe (S208F; 612732.0010) and arg328 to cys (R328C; 612732.0011). In the affected members of the other 3 families, 2 previously reported mutations, R331W (612732.0001) and R447C (612732.0009), were shown to coexist on 1 allele. This was the first report of patients carrying 2 HCP-related mutations on the same allele.
Harderoporphyria
In the 3 affected sibs with harderoporphyria (HARPO; 618892) reported by Nordmann et al. (1983), Lamoril et al. (1995) demonstrated homozygosity for a K404E missense mutation in exon 6 of the CPO gene (see 612732.0003).
Schmitt et al. (2005) reported the fifth known patient (from a third family) with harderoporphyria and demonstrated homozygosity for the K404E mutation.
In a Turkish male infant, born of consanguineous parents, with harderoporphyria, Hasanoglu et al. (2011) identified a homozygous H327R mutation in the CPOX gene (612732.0014).
Schmitt et al. (2005) noted that all 5 reported patients (from 3 families) with harderoporphyria had a K404E mutation (612732.0003) in homozygosity or compound heterozygosity with a null mutation. Biochemical and expression studies revealed that only a few missense mutations, restricted to 5 amino acids encoded by exon 6 (D400-K404), may accumulate significant amounts of harderoporphyrin. All types of mutations occurring elsewhere throughout the CPOX gene resulted in coproporphyrin accumulation and subsequently typical HCP. They stated that this was the first metabolic disorder in which clinical expression of overt disease depended on the location and type of mutation, resulting either in acute hepatic or in erythropoietic porphyria.
In a Turkish male infant, born of consanguineous parents, with harderoporphyria, Hasanoglu et al. (2011) identified a homozygous H327R mutation in the CPOX gene (612732.0014). The mutation occurred at a highly conserved residue involved in the enzyme's conversion of harderoporphyrinogen to protoporphyrinogen IX. The unaffected parents and an unaffected brother were all heterozygous for the mutation. Functional studies of the variant were not performed, but structural analysis suggested that it would alter the enzyme's structure and affect the second decarboxylation step. The findings expanded the genotype/phenotype correlations for this disease.
By study of somatic cell hybrids, Grandchamp et al. (1983) assigned the coproporphyrinogen oxidase locus (CPO) to chromosome 9.
In a patient previously reported by Grandchamp et al. (1977) and thought to have homozygous coproporphyria (HCP; 121300), Martasek et al. (1994) demonstrated a point mutation resulting in substitution of tryptophan for arginine. Both parents were heterozygous for the mutation. Martasek et al. (1994) referred to this mutation as ARG231TRP (R231W). Based on the initiation when described by Delfau-Larue et al. (1994), Lamoril et al. (2001) renumbered this mutation as R331W and showed that it can cause HCP in the heterozygous state as well.
In a Czech patient with a heterozygous form of hereditary coproporphyria (HCP; 121300), Delfau-Larue et al. (1994) found a G-to-A transition in the last nucleotide of exon 6 of the CPO gene. The exon 6/intron 6 junction was found to be CCA/gta rather than the normal CCG/gta. The mutation resulted in abnormal splicing and skipping of exon 6.
In the kindred reported by Nordmann et al. (1983) in which 3 sibs had harderoporphyria (HARPO; 618892), Lamoril et al. (1995) found by sequencing cDNA and genomic DNA that the patients carried a point mutation resulting in a LYS304GLU substitution (now known as lys404-to-glu) in exon 6 and the absence of the normal allele, suggesting a homozygous state for the mutation. Enzymatic activity studies of protein expressed from normal and mutated CPO cDNA in E. coli demonstrated that the K404E amino acid substitution was responsible for both the decrease in the enzyme activity and the accumulation of harderoporphyrin. The Michaelis constant of the mutated enzyme was 10-fold higher than normal, suggesting that the lysine at position 304 is important for binding the substrate. A slightly increased sensitivity to thermal denaturation was also observed.
Lamoril et al. (1995) numbered this mutation on the basis of the sequence described by Taketani et al. (1994). Subsequently the mutation was referred to as K404E (Lamoril et al., 1998) based on the initiation codon described by Delfau-Larue et al. (1994).
Schmitt et al. (2005) reported the fifth known patient (from a third family) with harderoporphyria and demonstrated homozygosity for the K404E mutation.
Lamoril et al. (1997) demonstrated a novel heterozygous mutation in the CPO gene in each of 3 unrelated patients with hereditary coproporphyria (HCP; 121300). The diagnosis was based on the observation of typical clinical manifestations, increased excretions of delta-aminolevulinic acid and porphobilinogen in urine and coproporphyrin III in both feces and urine, and 50% decreased COX activity in lymphocytes. One patient had a 5-bp insertion GCGCA after nucleotide 129 (129ins5) This insertion was responsible for a frameshift with a stop codon occurring 93 codons downstream.
Lamoril et al. (1997) demonstrated a novel heterozygous mutation in the CPO gene in each of 3 unrelated patients with hereditary coproporphyria (HCP; 121300). The diagnosis was based on the observation of typical clinical manifestations, increased excretions of delta-aminolevulinic acid and porphobilinogen in urine and coproporphyrin III in both feces and urine, and 50% decreased COX activity in lymphocytes. One patient was found to have a 21-bp in-frame deletion after nucleotide 483 in exon 1 (484del21).
Lamoril et al. (1997) demonstrated a novel mutation in the CPO gene in each of 3 unrelated patients with hereditary coproporphyria (HCP; 121300). The diagnosis was based on the observation of typical clinical manifestations, increased excretions of delta-aminolevulinic acid and porphobilinogen in urine and coproporphyrin III in both feces and urine, and 50% decreased COX activity in lymphocytes. One patient had a C-to-G transversion at nucleotide 883 in exon 4 that resulted in a his295-to-asp (H295D) substitution.
Lamoril et al. (1998) described a family with neonatal hemolytic anemia and harderoporphyria (HARPO; 618892). Affected members were compound heterozygotes for the lys404-to-glu (K404E) missense mutation (612732.0003) and a second allele that bore an A-to-G transition at the third position of the donor splice site in intron 6. This mutation resulted in skipping of exon 6 and the absence of functional protein. Lamoril et al. (1998) concluded that the K404E substitution, either in the homozygous or compound heterozygous state associated with the mutation leading to absence of functional mRNA or protein, is responsible for the specific clinical manifestations of harderoporphyria: jaundice, severe chronic hemolytic anemia of early onset associated with hepatosplenomegaly, and skin photosensitivity.
In a 38-year-old Japanese woman and her 22-year-old son with coproporphyria (HCP; 121300), Susa et al. (1998) demonstrated a C-to-T transition in exon 1 of the CPO gene at nucleotide position 85, which lies in the putative presequence for targeting to mitochondria. This mutation changed the codon for glutamine to a termination codon at amino acid position 29 (Q29X). MaeI restriction analysis showed 2 other carriers in the family. The C-to-T mutation was located within the putative alternative translation initiation codon (TIC-1), providing evidence that TIC-1 (Delfau-Larue et al., 1994) is the real TIC rather than TIC-2 (Taketani et al., 1994; Martasek et al., 1994).
Lamoril et al. (2001) identified a 1339C-T mutation in exon 7 of the CPO gene, resulting in an arg447-to-cys (R447C) substitution, in association with coproporphyria (HCP; 121300). Wiman et al. (2002) found the R447C mutation and the R331W mutation (612732.0001) in exon 5 on the same allele in patients with coproporphyria.
Wiman et al. (2002) identified a heterozygous 623C-T mutation in exon 2 of the CPO gene, resulting in a ser208-to-phe (S208F) substitution, in a patient with hereditary coproporphyria (HCP; 121300).
Wiman et al. (2002) identified a heterozygous 982C-T mutation in exon 5 of the CPO gene, resulting in an arg328-to-cys (R328C) substitution, in affected members of a family with hereditary coproporphyria (HCP; 121300).
Gross et al. (2002) reported an insertion of an adenine at nucleotide 857 in exon 4 of the CPO gene in a symptomatic patient with coproporphyria (HCP; 121300) and her father.
Akagi et al. (2006) described a Caucasian male who had symptoms of acute porphyria, with increases in urinary delta-aminolevulinic acid (ALA), porphobilinogen (PBG), and coproporphyrin that were consistent with hereditary coproporphyria (HCP; 121300). However, a greater than expected increase in ALA compared with PBG and a substantial increase in erythrocyte zinc protoporphyrin suggested additional ALA dehydratase (ALAD) deficiency (612740). Akagi et al. (2006) detected a heterozygous G-to-C transversion at nucleotide 835 of the CPO gene that caused a gly279-to-arg (G279R) amino acid change. The mutant protein expressed in E. coli was unstable and produced about 5% of activity compared with the wildtype. A missense mutation was found on 1 allele of the ALAD gene (125270.0006). Thus, the patient represented the first case of porphyria in which both CPO and ALAD deficiencies were demonstrated at the molecular level.
In a Turkish male infant, born of consanguineous parents, with harderoporphyria (HARPO; 618892), Hasanoglu et al. (2011) identified a homozygous c.980A-G transition in exon 5 of the CPOX gene, resulting in a his327-to-arg (H327R) substitution at a highly conserved residue involved in the enzyme's conversion of harderoporphyrinogen to protoporphyrinogen IX. The patient presented with neonatal jaundice, hemolytic anemia, and severe cutaneous photosensitivity. At age 1.5 months, he had an acute porphyric attack characterized by hepatosplenomegaly, elevated liver enzymes, red urine, metabolic acidosis, and severe Coombs-negative hemolytic anemia. The child died at age 5 months. Laboratory studies showed increased urinary porphyrins, increased aminolevulinic acid, and porphobilinogen; fecal porphyrins were not measured. The unaffected parents and an unaffected brother were all heterozygous for the mutation. Functional studies of the variant were not performed, but structural analysis suggested that it would alter the enzyme's structure and affect the second decarboxylation step.
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Cacheux, V., Martasek, P., Fougerousse, F., Delfau, M. H., Druart, L., Tachdjian, G., Grandchamp, B. Localization of the human coproporphyrinogen oxidase gene to chromosome band 3q12. Hum. Genet. 94: 557-559, 1994. [PubMed: 7959694] [Full Text: https://doi.org/10.1007/BF00211026]
Delfau-Larue, M.-H., Martasek, P., Grandchamp, B. Coproporphyrinogene (sic) oxidase: gene organization and description of a mutation leading to exon 6 skipping. Hum. Molec. Genet. 3: 1325-1330, 1994. [PubMed: 7987309] [Full Text: https://doi.org/10.1093/hmg/3.8.1325]
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Lamoril, J., Martasek, P., Deybach, J.-C., Da Silva, V., Grandchamp, B., Nordmann, Y. A molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria, a variant form of hereditary coproporphyria. Hum. Molec. Genet. 4: 275-278, 1995. [PubMed: 7757079] [Full Text: https://doi.org/10.1093/hmg/4.2.275]
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Lamoril, J., Puy, H., Whatley, S. D., Martin, C., Woolf, J. R., Da Silva, V., Deybach, J.-C., Elder, G. H. Characterization of mutations in the CPO gene in British patients demonstrates absence of genotype-phenotype correlation and identifies relationship between hereditary coproporphyria and harderoporphyria. Am. J. Hum. Genet. 68: 1130-1138, 2001. [PubMed: 11309681] [Full Text: https://doi.org/10.1086/320118]
Martasek, P., Camadro, J. M., Delfau-Larue, M.-H., Dumas, J.-B., Montagne, J. J., De Verneuil, H., Labbe, P., Grandchamp, B. Molecular cloning, sequencing, and functional expression of a cDNA encoding human coproporphyrinogen oxidase. Proc. Nat. Acad. Sci. 91: 3024-3028, 1994. [PubMed: 8159699] [Full Text: https://doi.org/10.1073/pnas.91.8.3024]
Martasek, P., Nordmann, Y., Grandchamp, B. Homozygous hereditary coproporphyria caused by an arginine to tryptophane substitution in coproporphyrinogen oxidase and common intragenic polymorphisms. Hum. Molec. Genet. 3: 477-480, 1994. [PubMed: 8012360] [Full Text: https://doi.org/10.1093/hmg/3.3.477]
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Schmitt, C., Gouya, L., Malonova, E., Lamoril, J., Camadro, J.-M., Flamme, M., Rose, C., Lyoumi, S., Da Silva, V., Boileau, C., Grandchamp, B., Beaumont, C., Deybach, J.-C., Puy, H. Mutations in human CPO gene predict clinical expression of either hepatic hereditary coproporphyria or erythropoietic harderoporphyria. Hum. Molec. Genet. 14: 3089-3098, 2005. [PubMed: 16159891] [Full Text: https://doi.org/10.1093/hmg/ddi342]
Susa, S., Daimon, M., Kondo, H., Kondo, M., Yamatani, K., Sasaki, H. Identification of a novel mutation of the CPO gene in a Japanese hereditary coproporphyria family. Am. J. Med. Genet. 80: 204-206, 1998. [PubMed: 9843038]
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Wiman, A., Floderus, Y., Harper, P. Two novel mutations and coexistence of the 991C-T and the 1339C-T mutation on a single allele in the coproporphyrinogen oxidase gene in Swedish patients with hereditary coproporphyria. J. Hum. Genet. 47: 407-412, 2002. [PubMed: 12181641] [Full Text: https://doi.org/10.1007/s100380200059]