HGNC Approved Gene Symbol: ADK
SNOMEDCT: 763721006;
Cytogenetic location: 10q22.2 Genomic coordinates (GRCh38): 10:74,151,221-74,709,290 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q22.2 | Hypermethioninemia due to adenosine kinase deficiency | 614300 | Autosomal recessive | 3 |
The ADK gene encodes adenosine kinase (ATP:adenosine 5-prime-phosphotransferase; EC 2.7.1.20), an abundant enzyme in mammalian tissues that catalyzes the transfer of the gamma-phosphate from ATP to adenosine, thereby serving as a potentially important regulator of concentrations of both extracellular adenosine and intracellular adenine nucleotides. Adenosine has widespread effects on the cardiovascular, nervous, respiratory, and immune systems, and inhibitors of ADK could play an important pharmacologic role in increasing intravascular adenosine concentrations and acting as inflammatory agents (summary by Spychala et al., 1996).
Spychala et al. (1996) obtained full-length cDNA clones encoding catalytically active ADK from lymphocyte, placental, and liver cDNA libraries. On Northern blots of all tissues examined, they identified mRNA species of 1.3 and 1.8 kb, attributable to alternative polyadenylation sites at the 3-prime end of the gene. The encoded protein consisted of 345 amino acids with a calculated molecular size of 38.7 kD and without any sequence similarities to other well-characterized mammalian nucleoside kinases. In contrast, 2 regions were identified with significant sequence identity to microbial ribokinase and fructokinases and a bacterial inosine/guanosine kinase. Thus, ADK is a structurally distinct mammalian nucleoside kinase that appears to be akin to sugar kinases of microbial origin.
McNally et al. (1997) also cloned human cDNAs encoding adenosine kinase. They found cDNAs encoding both the 345-amino acid form and a 362-amino acid form of the enzyme. These 2 alternately spliced forms differed only at the 5-prime end. When expressed, both isoforms of the enzyme phosphorylated adenosine with identical kinetics and both required Mg2+ for activity.
The structural gene for this enzyme was tentatively assigned to chromosome 10 by somatic cell hybrid studies (Klobutcher et al., 1976). By the principle of gene dosage, Francke and Thompson (1979) concluded by exclusion that ADK must be in the region 10q11-10q24.
In a case of trisomy 10p, Snyder et al. (1984) found normal levels of ADK.
By exome sequencing, Bjursell et al. (2011) identified a homozygous mutation in the ADK gene (102750.0001) in 2 Swedish sibs with severe developmental delay, mild liver dysfunction, and persistent hypermethioninemia due to adenosine kinase deficiency (614300). Subsequent analysis of this gene in Malaysian patients with a similar phenotype revealed 2 different homozygous mutations in the ADK gene (102750.0002 and 102750.0003) in 2 families. The phenotype was characterized by global developmental delay, early-onset seizures, mild dysmorphic features, and characteristic biochemical anomalies, including persistent hypermethioninemia with increased levels of S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy); homocysteine was typically normal. Bjursell et al. (2011) concluded that the phenotype resulted from a combination of direct adenosine toxicity, a defect in the regulation of adenosine, and disruption of a wide range of methyltransferase reactions.
In a large consanguineous Iranian family (M173) in which 6 individuals had mild to moderate mental retardation and autism spectrum disorder mapped to a 9.7-Mb candidate region on chromosome 10 between SNPs rs1599711 and rs942793 (formerly designated MRX8), Najmabadi et al. (2007) identified a homozygous his324-to-arg (H324R; 102750.0004) substitution in the ADK gene. However, no additional clinical information was provided, and no metabolic studies of the patients or functional studies of the variant were performed. It was thus unclear whether the phenotype in this family was hypermethioninemia due to ADK deficiency.
Neonatal hepatic steatosis (228100) is a fatal condition characterized by rapid microvesicular fat infiltration and enlargement of the liver, which shows a pale and yellowish coloration. Microvesicular fat infiltration, liver failure, coma, and death are considered to be a consequence of severe impairment of mitochondrial function. Boison et al. (2002) pursued the hypothesis that a deficit in adenosine-dependent metabolism is a causative factor for the development of microvesicular hepatic steatosis. A deficiency of adenosine kinase, the major adenosine-removing enzyme of postnatal liver, was expected to affect liver function on 3 levels: availability of adenine nucleotides; disruption of the futile cycle between AMP and adenosine; and maintenance of transmethylation reactions. Homozygous Adk -/- mice, generated through Adk targeting of embryonic stem cells, developed normally during embryogenesis. However, within 4 days after birth they displayed microvesicular hepatic steatosis and died within 14 days with fatty liver. Adenine nucleotides were decreased and S-adenosylhomocysteine, a potent inhibitor of transmethylation reactions, was increased in the mutant liver. Thus, a deficiency of adenosine metabolism is identified as a powerful contributor to the development of neonatal hepatic steatosis, providing a model for the rapid development of postnatally lethal fatty liver.
In 2 Swedish sibs with hypermethioninemia due to adenosine kinase deficiency (614300), Bjursell et al. (2011) identified a homozygous 902C-A transversion in the ADK gene, resulting in an ala301-to-glu (A301E) substitution adjacent to the catalytic site. Each unaffected parent was heterozygous for the mutation, which was not found in 105 controls. In vitro functional expression studies in E. coli showed that the mutant protein had almost no enzymatic activity.
In 2 Malaysian sibs with hypermethioninemia due to adenosine kinase deficiency (614300), Bjursell et al. (2011) identified a homozygous 653A-C transversion in the ADK gene, resulting in an asp218-to-ala (D218A) substitution in the central beta-sheet domain. Each unaffected parent was heterozygous for the mutation. In vitro functional expression studies in E. coli showed that the mutant protein had about 20% residual enzymatic activity compared to wildtype.
In 2 Malaysian sibs with hypermethioninemia due to adenosine kinase deficiency (614300), Bjursell et al. (2011) identified a homozygous 38G-A transition in the ADK gene, resulting in a gly13-to-glu (G13E) substitution close to the binding site for adenosine. Each unaffected parent was heterozygous for the mutation. In vitro functional expression studies in E. coli showed that the mutant protein had about 10% residual enzymatic activity compared to wildtype.
This variant is classified as a variant of unknown significance because it is unclear whether the phenotype in the family (M173) reported by Najmabadi et al. (2007) was hypermethioninemia due to adenosine kinase deficiency (614300).
In a large consanguineous Iranian family (M173) in which 6 individuals had mild to moderate mental retardation and autism spectrum disorder mapped to a 9.7-Mb candidate region on chromosome 10 between SNPs rs1599711 and rs942793 (formerly designated MRT8), Najmabadi et al. (2007) identified a homozygous his324-to-arg (H324R) substitution in the ADK gene. No additional clinical information was provided, and no metabolic studies of the patients or functional studies of the variant were performed.
Bjursell, M. K., Blom, H. J., Cayuela, J. A., Engvall, M. L., Lesko, N., Balasubramaniam, S., Brandberg, G., Halldin, M., Falkenberg, M., Jakobs, C., Smith, D., Struys, E., von Dobeln, U., Gustafsson, C. M., Lundeberg, J., Wedell, A. Adenosine kinase deficiency disrupts the methionine cycle and causes hypermethioninemia, encephalopathy, and abnormal liver function. Am. J. Hum. Genet. 89: 507-515, 2011. [PubMed: 21963049] [Full Text: https://doi.org/10.1016/j.ajhg.2011.09.004]
Boison, D., Scheurer, L., Zumsteg, V., Rulicke, T., Litynski, P., Fowler, B., Brandner, S., Mohler, H. Neonatal hepatic steatosis by disruption of the adenosine kinase gene. Proc. Nat. Acad. Sci. 99: 6985-6990, 2002. [PubMed: 11997462] [Full Text: https://doi.org/10.1073/pnas.092642899]
Chan, T.-S., Creagan, R. P., Reardon, M. P. Adenosine kinase as a new selective marker in somatic cell genetics: isolation of adenosine kinase-deficient mouse cell lines and human-mouse hybrid cell lines containing adenosine kinase. Somat. Cell Genet. 4: 1-12, 1978. [PubMed: 204068] [Full Text: https://doi.org/10.1007/BF01546489]
Francke, U., Thompson, L. Regional mapping, by exclusion, of adenosine kinase (ADK) on human chromosome 10 using the gene dosage approach. (Abstract) Cytogenet. Cell Genet. 25: 156, 1979.
Klobutcher, L. A., Nichols, E. A., Kucherlapati, R. S., Ruddle, F. H. Assignment of the gene for human adenosine kinase to chromosome 10 using a somatic cell hybrid clone panel. Cytogenet. Cell Genet. 16: 171-174, 1976. [PubMed: 185014] [Full Text: https://doi.org/10.1159/000130582]
McNally, T., Helfrich, R. J., Cowart, M., Dorwin, S. A., Meuth, J. L., Idler, K. B., Klute, K. A., Simmer, R. L., Kowaluk, E. A., Halbert, D. N. Cloning and expression of the adenosine kinase gene from rat and human tissues. Biochem. Biophys. Res. Commun. 231: 645-650, 1997. [PubMed: 9070863] [Full Text: https://doi.org/10.1006/bbrc.1997.6157]
Najmabadi, H., Motazacker, M. M., Garshasbi, M., Kahrizi, K., Tzschach, A., Chen, W., Behjati, F., Hadavi, V., Nieh, S. E., Abedini, S. S., Vazifehmand, R., Firouzabadi, S. G., and 9 others. Homozygosity mapping in consanguineous families reveals extreme heterogeneity of non-syndromic autosomal recessive mental retardation and identifies 8 novel gene loci. Hum. Genet. 121: 43-48, 2007. [PubMed: 17120046] [Full Text: https://doi.org/10.1007/s00439-006-0292-0]
Snyder, F. F., Lin, C. C., Rudd, N. L., Shearer, J. E., Heikkila, E. M., Hoo, J. J. A de novo case of trisomy 10p: gene dosage studies of hexokinase, inorganic pyrophosphatase and adenosine kinase. Hum. Genet. 67: 187-189, 1984. [PubMed: 6146563] [Full Text: https://doi.org/10.1007/BF00272998]
Spychala, J., Datta, N. S., Takabayashi, K., Datta, M., Fox, I., Gribbin, T., Mitchell, B. Cloning of human adenosine kinase cDNA: sequenced similarity to microbial ribokinases and fructokinases, Proc. Nat. Acad. Sci. 93: 1232-1237, 1996. [PubMed: 8577746] [Full Text: https://doi.org/10.1073/pnas.93.3.1232]