Alternative titles; symbols
HGNC Approved Gene Symbol: TKFC
Cytogenetic location: 11q12.2 Genomic coordinates (GRCh38) : 11:61,333,228-61,353,426 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q12.2 | Triokinase and FMN cyclase deficiency syndrome | 618805 | Autosomal recessive | 3 |
DAK has bifunctional activity: it catalyzes the reaction flavin adenine dinucleotide (FAD) to riboflavin 4-prime,5-prime-phosphate (cyclic flavin mononucleotide, or cFMN), in addition to ATP-dependent phosphorylation of dihydroxyacetone (DHA) (Cabezas et al., 2005).
By searching a database for sequences similar to purified rat liver FMN cyclase, followed by PCR of a brain cDNA library, Cabezas et al. (2005) cloned human DAK, which they called DHA kinase/FMN cyclase. The deduced protein contains 575 amino acids and shares 84 to 99% identity with its mammalian orthologs. It also has orthologs in several lower organisms. SDS-PAGE detected recombinant human DAK at an apparent molecular mass of 59.4 kD.
Cabezas et al. (2005) determined that the DAK gene contains 17 exons.
By genomic sequence analysis, Cabezas et al. (2005) mapped the TKFC gene to chromosome 11q12.2.
Cabezas et al. (2005) found that both recombinant human DAK and purified rat liver FMN cyclase catalyzed phosphorylation of DHA and formation of cFMN. In addition, each activity of human DAK was inhibited by the substrates of the other: ATP and dihydroxyacetone were strong and weak inhibitors of FMN cyclase activity, respectively, whereas FAD was a weak, but likely full, inhibitor of DHA kinase activity. Cabezas et al. (2005) observed that the 2 activities of DAK were related, but they reasoned that the active sites may not fully coincide, since DHA was only a partial inhibitor of FMN cyclase activity.
In 2 sib pairs from 2 unrelated consanguineous families with triokinase and FMN cyclase deficiency syndrome (TKFCD; 618805), Wortmann et al. (2020) identified homozygosity for missense mutations in the TKFC gene, R543I (615844.0001) and G445S (615844.0002), respectively.
In 2 sisters (family 1) with triokinase and FMN cyclase deficiency syndrome (TKFCD; 618805), Wortmann et al. (2020) identified homozygosity for a c.1628G-T transversion (c.1628G-T, NM_015533.3) in the TKFC gene, resulting in an arg543-to-ile (R543I) substitution at an evolutionarily conserved residue within the FMN lyase (L) domain, affecting the cFMN synthase domain. Their unaffected first-cousin parents of Gujarati origin were heterozygous for the mutation, which was also present in heterozygosity in the gnomAD database at a minor allele frequency of 2.40 x 10(-5). Both sisters had congenital cataract, but otherwise exhibited disparate phenotypes: the older sister had developmental delay with speech delay, wide-based gait, and cerebellar hypoplasia, whereas the younger sister failed to thrive from the neonatal period and died at age 11 weeks with abnormal liver function, lactic acidosis, and dilated cardiomyopathy. Her brain MRI was normal, whereas the older sister's cardiac evaluation was normal. Western blot of patient cultured skin fibroblasts showed a significant reduction in TKFC protein compared to control fibroblasts. Quantification of TKFC activity in E. coli cells showed a reduction to less than 2% or approximately 6% with the R543I mutant compared to wildtype TKFC, when D-glyceraldehyde or dihydroxyacetone was used as substrate, respectively. Functional analysis in yeast cells demonstrated that wildtype human TKFC could use dihydroxyacetone (DHA) as a carbon source, whereas yeast cells overexpressing the TKFC mutant failed to grow on DHA as a carbon source.
In a Turkish brother and sister (family 2) with triokinase and FMN cyclase deficiency syndrome (TKFCD; 618805), Wortmann et al. (2020) identified homozygosity for a c.1333G-A transition (c.1333G-A, NM_015533.3) in the TKFC gene, resulting in a gly445-to-ser (G445S) substitution at an evolutionarily conserved residue within the FMN lyase (L) domain. Their unaffected consanguineous parents were heterozygous for the mutation, which was not found in the gnomAD database. The brother had failure to thrive from early infancy, with diarrhea, oral hypersensitivity, and liver failure; attempts at enteral feeding via gastrostomy tube failed, and he was dependent on parenteral feeding from the age of 34 months. Evaluation at age 22 months revealed global developmental delay as well as bilateral cataracts. At 3 years 10 months of age, he was below the first percentile for height and weight, was unable to walk unassisted, and had no words. His older sister, in contrast, had delayed speech and learning difficulties but was otherwise well and did not exhibit cataract. Quantification of TKFC activity in E. coli cells showed a reduction to less than 2% or approximately 6% with the G445S mutant compared to wildtype TKFC, when D-glyceraldehyde or dihydroxyacetone was used as substrate, respectively. Functional analysis in yeast cells demonstrated that wildtype human TKFC could use dihydroxyacetone (DHA) as a carbon source, whereas yeast cells overexpressing the TKFC mutant failed to grow on DHA as a carbon source.
Cabezas, A., Costas, M. J., Pinto, R. M., Couto, A., Cameselle, J. C. Identification of human and rat FAD-AMP lyase (cyclic FMN forming) as ATP-dependent dihydroxyacetone kinases. Biochem. Biophys. Res. Commun. 338: 1682-1689, 2005. [PubMed: 16289032] [Full Text: https://doi.org/10.1016/j.bbrc.2005.10.142]
Wortmann, S. B., Meunier, B., Mestek-Boukhibar, L., van den Broek, F., Maldonado, E. M., Clement, E., Weghuber, D., Spenger, J., Jaros, Z., Taha, F., Yue, W. W., Heales, S. J., Davison, J. E., Mayr, J. A., Rahman, S. Bi-allelic variants in TKFC encoding triokinase/FMN cyclase are associated with cataracts and multisystem disease. Am. J. Hum. Genet. 106: 256-263, 2020. [PubMed: 32004446] [Full Text: https://doi.org/10.1016/j.ajhg.2020.01.005]