Alternative titles; symbols
HGNC Approved Gene Symbol: PNPO
SNOMEDCT: 724576005;
Cytogenetic location: 17q21.32 Genomic coordinates (GRCh38) : 17:47,941,571-47,949,308 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.32 | Pyridoxamine 5'-phosphate oxidase deficiency | 610090 | Autosomal recessive | 3 |
Vitamin B6, or pyridoxal 5-prime-phosphate (PLP), is critical for normal cellular function, and some cancer cells have notable differences in vitamin B6 metabolism compared to their normal counterparts. The rate-limiting enzyme in vitamin B6 synthesis is pyridoxine 5-prime-phosphate (PNP) oxidase (PNPO; EC 1.4.3.5).
Ngo et al. (1998) isolated a PNPO clone from a rat liver library. They found that the predicted 30-kD protein contained the PNPO signature motif found in the PNPO of S. cerevisiae and bacteria and 5 predicted protein kinase C (see 176960) phosphorylation sites.
Kang et al. (2004) cloned full-length PNPO from a whole brain cDNA library. The deduced 261-amino acid protein has a calculated molecular mass of 30 kD. Posttranslational modification sites include a sulfation site, 9 phosphorylation sites, 3 N-myristoylation sites, and an RGD cell attachment sequence. PNPO shares 90% amino acid identity with mouse Pnpo. Northern blot analysis detected transcripts of 2.4 and 3.4 kb in all human tissues examined, with the difference in transcript size due to use of alternative polyadenylation sites. Highest expression was in liver, followed by skeletal muscle and kidney. Western blot analysis detected a 30-kD protein in all tissues and cell lines examined.
PNPO activity is developmentally regulated in rat liver, being low in fetal liver and high in adult liver. Ngo et al. (1998) showed that PNPO expression was similarly developmentally regulated in rat brain. Additionally, Ngo et al. (1998) demonstrated that, analogous to rodent hepatomas, PNPO expression in rodent brain tumors was comparable to or lower than that present in fetal rat brain. However, the human neuroblastoma cell lines examined displayed variable PNPO activity; a human hepatocellular carcinoma cell line contained relatively high PNPO activity, comparable to that found in normal human liver.
Kang et al. (2004) characterized the enzymatic properties of recombinant PNPO following expression in E. coli. PNPO converted both PNP and pyridoxamine 5-prime-phosphate to PLP, and the PLP product was an inhibitor. Mutation analysis indicated that the first N-terminal conserved helix segment and the C-terminal 25 residues were required for enzymatic activity.
Kang et al. (2004) determined that the PNPO gene contains 7 exons and spans 7.7 kb. The promoter region shows characteristics of housekeeping genes, with a CpG island and Sp1 (189906)-binding sites, but no TATA-like sequences.
By genomic sequence analysis, Kang et al. (2004) mapped the PNPO gene to chromosome 17q21.32. They mapped the mouse gene to chromosome 11.
In 5 patients from 3 families with PNPO deficiency (PNPOD; 610090), Mills et al. (2005) identified homozygous missense, splice site, and stop codon mutations in the PNPO gene. Expression studies in Chinese hamster ovary cells showed that the splice site (IVS3-1G-A; 603287.0002) and stop codon (X262Q; 603287.0003) mutations were null activity mutations and that the missense mutation (R229W; 603287.0001) markedly reduced pyridox(am)ine phosphate oxidase activity. The authors suggested that maintenance of optimal PLP levels in the brain may be important in many neurologic disorders in which neurotransmitter metabolism is disturbed (either as a primary or as a secondary phenomenon).
In 11 patients from 7 unrelated families with PNPOD, Plecko et al. (2014) identified 3 different biallelic mutations in the PNPO gene; 6 of the families carried the same homozygous missense mutation (R225H; 603287.0005). The 6 families derived from the former Yugoslavia. In vitro functional expression studies in CHO cells showed that the R225H mutant protein had no detectable enzyme activity. Most of the patients had a partial or even complete response to pyridoxine treatment.
In 2 unrelated boys with PNPOD, Ware et al. (2014) identified 2 different homozygous missense mutations in the PNPO gene (603287.0005 and 603287.0006). Functional studies of the variants were not performed.
In twin boys, the children of consanguineous Turkish parents, with PNPO deficiency (PNPOD; 610090), Mills et al. (2005) detected a homozygous C-to-T transition in exon 7 of the PNPO gene, resulting in a substitution of tryptophan for the conserved arginine-229 residue (R229W). At least 4 and possibly 6 sibs from this family, including the twins, died from the same disorder. Brautigam et al. (2002) had described the clinical and laboratory findings in these patients.
In an infant with PNPO deficiency (PNPOD; 610090), Mills et al. (2005) found a splice mutation in intron 3 (IVS3-1G-A) on 1 allele of the PNPO gene. The missense mutation carried by the other allele was considered to be a polymorphism. The parents were second cousins of East African Asian origin. Patient fibroblast mRNA lacked exon 4, confirming aberrant splicing. This patient was the only one studied by Mills et al. (2005) to receive PLP treatment and to survive beyond the neonatal period, but showed persistent central hypotonia and painful dystonic spasms as well as some seizures by the second year of life. He had marked acquired microcephaly and moderate to severe developmental delay.
In 2 affected sibs from a consanguineous Pakistani family with PNPO deficiency (PNPOD; 610090), Mills et al. (2005) detected a homozygous T-to-C transition in exon 7 of the PNPO gene that resulted in substitution of glutamine for the stop codon at position 262 (X262Q) and the addition of 28 amino acids. Expression studies demonstrated that X262Q PNPO is a null activity mutant.
In a male infant with PNPO deficiency (PNPOD; 610090), Ruiz et al. (2008) identified a homozygous 520C-T transition in exon 5 of the PNPO gene, resulting in an ala174-to-ter (A174X) substitution. The patient had severe seizures and myoclonus within the first hours of life and died at age 48 days.
In 8 patients from 6 unrelated families with pyridoxamine 5-prime-phosphate oxidase deficiency (PNPOD; 610090), Plecko et al. (2014) identified a homozygous c.674G-A transition (c.674G-A, NM_001182.3) in exon 7 of the PNPO gene, resulting in an arg225-to-his (R225H) substitution at a conserved region in the PLP binding site. The mutation, which segregated with the disorder in the families, was not found in 100 control alleles. In vitro functional expression studies in CHO cells showed that the R225H mutant protein had no detectable enzyme activity. Most of the patients had a partial or even complete response to pyridoxine treatment. The 6 families derived from the former Yugoslavia.
In a 7-year-old Greek boy with PNPOD, Ware et al. (2014) identified a homozygous R225 substitution in the PNPO gene. Each unaffected parent was heterozygous for the mutation. Functional studies of the variant were not performed. The patient showed an initial response to treatment with pyridoxine, and later showed a sustained therapeutic response to monotherapy with high-dose pyridoxal 5-prime phosphate (PLP). Ware et al. (2014) hypothesized that some degree of pyridoxine 5-prime-phosphate binding was preserved in the mutant protein, resulting in pyridoxine responsiveness.
In a 21-month-old male infant, born of consanguineous Sudanese parents, with pyridoxamine 5-prime-phosphate oxidase deficiency (PNPOD; 610090), Ware et al. (2014) identified a homozygous c.686G-A transition in the PNPO gene, resulting in an arg229-to-gln (R229Q) substitution. Each unaffected parent was heterozygous for the mutation. Functional studies of the variant were not performed, but a different mutation affecting this same codon has been reported (R229W; 603287.0001). The patient showed good initial and sustained response to high doses of pyridoxal 5-prime-phosphate treatment.
Brautigam, C., Hyland, K., Wevers, R., Sharma, R., Wagner, L., Stock, G.-J., Heitmann, F., Hoffmann, G. F. Clinical and laboratory findings in twins with neonatal epileptic encephalopathy mimicking aromatic L-amino acid decarboxylase deficiency. Neuropediatrics 33: 113-117, 2002. [PubMed: 12200739] [Full Text: https://doi.org/10.1055/s-2002-33673]
Kang, J. H., Hong, M.-L., Kim, D. W., Park, J., Kang, T.-C., Won, M. H., Baek, N.-I., Moon, B. J., Choi, S. Y., Kwon, O.-S. Genomic organization, tissue distribution and deletion mutation of human pyridoxine 5-prime-phosphate oxidase. Europ. J. Biochem. 271: 2452-2461, 2004. [PubMed: 15182361] [Full Text: https://doi.org/10.1111/j.1432-1033.2004.04175.x]
Mills, P. B., Surtees, R. A. H., Champion, M. P., Beesley, C. E., Dalton, N., Scambler, P. J., Heales, S. J. R., Briddon, A., Schmeimberg, I., Hoffmann, G. F., Zschocke, J., Clayton, P. T. Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5-prime-phosphate oxidase. Hum. Molec. Genet. 14: 1077-1086, 2005. [PubMed: 15772097] [Full Text: https://doi.org/10.1093/hmg/ddi120]
Ngo, E. O., LePage, G. R., Thanassi, J. W., Meisler, N., Nutter, L. M. Absence of pyridoxine-5-prime-phosphate oxidase (PNPO) activity in neoplastic cells: isolation, characterization, and expression of PNPO cDNA. Biochemistry 37: 7741-7748, 1998. [PubMed: 9601034] [Full Text: https://doi.org/10.1021/bi972983r]
Plecko, B., Paul, K., Mills, P., Clayton, P., Paschke, E., Maier, O., Hasselmann, O., Schmiedel, G., Kanz, S., Connolly, M., Wolf, N., Struys, E., Stockler, S., Abela, L., Hofer, D. Pyridoxine responsiveness in novel mutations of the PNPO gene. Neurology 82: 1425-1433, 2014. [PubMed: 24658933] [Full Text: https://doi.org/10.1212/WNL.0000000000000344]
Ruiz, A., Garcia-Villoria, J., Ormazabal, A., Zschocke, J., Fiol, M., Navarro-Sastre, A., Artuch, R., Vilaseca, M. A., Ribes, A. A new fatal case of pyridox(am)ine 5-prime-phosphate oxidase (PNPO) deficiency. Molec. Genet. Metab. 93: 216-218, 2008. [PubMed: 18024216] [Full Text: https://doi.org/10.1016/j.ymgme.2007.10.003]
Ware, T. L., Earl, J., Salomons, G. S., Struys, E. A., Peters, H. L., Howell, K. B., Pitt, J. J., Freeman, J. L. Typical and atypical phenotypes of PNPO deficiency with elevated CSF and plasma pyridoxamine on treatment. Dev. Med. Child Neurol. 56: 498-502, 2014. [PubMed: 24266778] [Full Text: https://doi.org/10.1111/dmcn.12346]