Alternative titles; symbols
HGNC Approved Gene Symbol: PDXK
Cytogenetic location: 21q22.3 Genomic coordinates (GRCh38): 21:43,719,129-43,762,299 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 21q22.3 | Neuropathy, hereditary motor and sensory, type VIC, with optic atrophy | 618511 | Autosomal recessive | 3 |
Pyridoxal kinase (PDXK; EC 2.7.1.35) converts vitamin B6 to pyridoxal-5-phosphate (PLP), an essential cofactor in the intermediate metabolism of amino acids and neurotransmitters (Hanna et al., 1997).
Hanna et al. (1997) cloned the cDNA encoding PDXK, which they referred to as PKH. The PDXK gene encodes a 312-amino acid polypeptide, and expression of the cDNA revealed pyridoxal kinase activity. Northern blot analysis revealed that a major 1.5-kb PDXK transcript was expressed in all tissues tested.
Using databases, Chelban et al. (2019) found that PDXK is highly expressed in peripheral nerve tissue, including peripheral sensory neurons. In 9 of 11 brain regions analyzed, PDXK was coexpressed with genes relating to synaptic transmission and neuronal identity, whereas coexpression data from the tibial nerve showed that PDXK was located within a module enriched for genes involved in oxidation-reduction processes.
Hanna et al. (1997) reported that a BAC clone from the human 21q22.3 region contains almost the entire PDXK gene on 10 distinct exons.
The expression of PDXK shows circadian oscillations. Gachon et al. (2004) found that the expression of Pdxk in mouse liver and brain is regulated by the 3 PAR bZIP transcription factors, Dbp (124097), Hlf (142385), and Tef (179020), which also show circadian oscillations in expression. Mice devoid of all 3 transcription factors showed decreased levels of brain PLP, serotonin, and dopamine, and were highly susceptible to generalized spontaneous and audiogenic epilepsies that were frequently lethal.
Tang et al. (2005) determined the crystal structure of sheep Pdxk in complex with the CDK inhibitor (R)-roscovitine and with 2 roscovitine derivatives designed not to interact with CDKs. All 3 roscovitines bound similarly in the pyridoxal-binding site of Pdxk rather than in the ATP-binding site.
Chern and Beutler (1976) concluded that alleles at a locus symbolized PNK determine the level of activity of pyridoxine kinase in erythrocytes: PNK(H) and PNK(L), for 'high' and 'low', respectively. The frequency of these 2 alleles was estimated to be 0.81 and 0.19 for whites and 0.35 and 0.65 for blacks. They suggested that the PNK(L) state of red cells is the result of a stability mutation.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Hereditary Motor and Sensory Neuropathy Type VIC with Optic Atrophy
In 4 patients from 2 unrelated families with hereditary motor and sensory neuropathy type VIC with optic atrophy (HMSN6C; 618511) Chelban et al. (2019) identified homozygous missense mutations in the PDXK gene (A228T, 179020.0001 and R220Q, 179020.0002). The mutations, which were found by a combination of whole-genome or whole-exome sequencing and homozygosity mapping and confirmed by Sanger sequencing, segregated with the disorder in the families. In vitro conformational analysis indicated that the A228T mutation induced changes around the catalytic pocket, hindering the enzyme's ability to bind ATP. Studies of cells derived from patients of both families showed decreased pyridoxal (PL) kinase activity compared to controls, and patients had decreased plasma PLP levels compared to controls. The findings were consistent with a loss-of-function effect.
In 2 sibs, born of unrelated Cypriot parents (family 1), with hereditary motor and sensory neuropathy type VIC with optic atrophy (HMSN6C; 618511), Chelban et al. (2019) identified a homozygous c.682G-A transition (c.682G-A, NM_003681) in the PDXK gene, resulting in an ala228-to-thr (A228T) substitution at a conserved residue in the ATP-binding pocket of the PL kinase. The mutation, which was found by a combination of whole-genome sequencing and homozygosity mapping and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in 150 Cypriot controls, but was found at a low frequency in the heterozygous state in the gnomAD database (7 of 250,586 alleles). Patient cells showed decreased PDXK enzymatic activity compared to controls.
In 2 sisters, born of unrelated Scottish (father) and Italian (mother) parents (family 2), with hereditary motor and sensory neuropathy type VIC with optic atrophy (HMSN6C; 618511), Chelban et al. (2019) identified a homozygous c.659G-A transition (c.659G-A, NM_003681) in the PDXK gene, resulting in an arg220-to-gln (R220Q) substitution at a conserved residue in the vicinity of the ATP-binding site. The mutation, which was found by a combination of whole-exome sequencing and homozygosity mapping and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found at a low frequency in the heterozygous state in the gnomAD database (5 of 250,146 alleles). Patient cells showed decreased PDXK enzymatic activity compared to controls.
Chelban, V., Wilson, M. P., Chardon, J. W., Vandrovcova, J., Zanetti, M. N., Zamba-Papanicolaou, E., Efthymiou, S., Pope, S., Conte, M. R., Abis, G., Liu, Y.-T., Tribollet, E., and 26 others. PDXK mutations cause polyneuropathy responsive to pyridoxal 5-prime-phosphate supplementation. Ann. Neurol. 86: 225-240, 2019. [PubMed: 31187503] [Full Text: https://doi.org/10.1002/ana.25524]
Chern, C. J., Beutler, E. Biochemical and electrophoretic studies of erythrocyte pyridoxine kinase in white and black Americans. Am. J. Hum. Genet. 28: 9-17, 1976. [PubMed: 2009]
Gachon, F., Fonjallaz, P., Damiola, F., Gos, P., Kodama, T., Zakany, J., Duboule, D., Petit, B., Tafti, M., Schibler, U. The loss of circadian PAR bZip transcription factors results in epilepsy. Genes Dev. 18: 1397-1412, 2004. [PubMed: 15175240] [Full Text: https://doi.org/10.1101/gad.301404]
Hanna, M. C., Turner, A. J., Kirkness, E. F. Human pyridoxal kinase: cDNA cloning, expression, and modulation by ligands of the benzodiazepine receptor. J. Biol. Chem. 272: 10756-10760, 1997. [PubMed: 9099727] [Full Text: https://doi.org/10.1074/jbc.272.16.10756]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Tang, L., Li, M.-H., Cao, P., Wang, F., Chang, W.-R., Bach, S., Reinhardt, J., Ferandin, Y., Galons, H., Wan, Y., Gray, N., Meijer, L., Jiang, T., Liang, D.-C. Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. J. Biol. Chem. 280: 31220-31229, 2005. [PubMed: 15985434] [Full Text: https://doi.org/10.1074/jbc.M500805200]