Alternative titles; symbols
HGNC Approved Gene Symbol: AK1
SNOMEDCT: 766982000;
Cytogenetic location: 9q34.11 Genomic coordinates (GRCh38): 9:127,866,480-127,879,621 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.11 | Hemolytic anemia due to adenylate kinase deficiency | 612631 | Autosomal recessive | 3 |
Adenylate kinase (EC 2.7.4.3) is a ubiquitous monomeric enzyme that catalyzes the reversible conversion of MgATP plus AMP to MgADP plus ADP and contributes to homeostasis of the adenine nucleotide composition in the cell (Matsuura et al., 1989).
By screening a human genomic library with chicken Ak1 cDNA, Matsuura et al. (1989) cloned the AK1 gene. The deduced protein contains 194 amino acids. Northern blot analysis of human skeletal muscle RNA revealed transcripts of 0.9 and 2.5 kb that differed in their 3-prime tails.
Matsuura et al. (1989) determined that the AK1 gene spans 12 kb and has 7 exons. The 5-prime flanking region contains a TATA box and 3 putative SP1 (189906)-binding sites within a GC-rich region, but it has no typical CAAT box. The 3-prime region contains 3 canonical polyadenylation signals. Alu sequences are located in the large intron 5 and in the noncoding region of exon 7.
Rapley et al. (1968) concluded that the AK locus is linked to the ABO (110300) locus with a recombination value of about 0.20. Schleutermann et al. (1969) found that the nail-patella syndrome locus (NPS1; 161200) and the AK locus are closely linked. No recombination was found in 53 opportunities. Fenger and Sorensen (1975) found a 1.33 to 1 ratio for the female to male recombination fractions between ABO and AK, but the difference between the recombination fractions was not significantly different from zero. All published data combined showed the most likely recombination fraction to be about 14%. Westerveld et al. (1976) found evidence that the AK locus assigned to chromosome 9 is the AK1 locus, or so-called red cell AK.
In an early instance of deletion mapping, Ferguson-Smith et al. (1976) localized the ABO-NPS1-AK1 linkage group to 9q34 by regional assignment of AK1 in studies of a chromosome deletion. Cook et al. (1978) collated evidence that ABO-AK1 lie in band 9q34. They could exclude MNSs, GPT, and Gc from chromosome 9. AK1 is proximal to the break in the Philadelphia chromosome rearrangement (Geurts van Kessel et al., 1982). On the basis of a chromosome 9 aberration, an inverted paracentric insertion, inv ins(9)(q22.1q34.3q34.1), Allderdice et al. (1986) concluded that AK1 is located in 9q34.1-q34.3. Since AK1 is in 9q34 and is proximal to the breakpoint that creates the Philadelphia chromosome in chronic myeloid leukemia, located in band 9q34.1, AK1 and probably the linked ABO locus may be in the proximal part of 9q34.1.
Fildes and Harris (1966) found electrophoretic variation in red cells and defined 3 phenotypes, designated AK1, AK2-1 and AK2. All of the 141 children of 2 AK1 parents (62 such matings) were also AK1. Among the 136 children of AK1 by AK2-1 matings, 72 were AK1 and 64 AK2-1. AK1 and AK2 persons were thought to be homozygotes for a 2-allele system and AK2-1 persons heterozygotes. The frequency of the rarer AK2 allele was about 0.05 in the English and about 1 in 400 persons would be expected to be homozygous for this allele. Survey and family data were consistent. Singer and Brock (1971) identified a probably silent allele at the AK locus.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
In a patient with hemolytic anemia and adenylate kinase deficiency (612631), Matsuura et al. (1989) identified an arg128-to-trp mutation (103000.0001) in the AK1 gene.
In 2 sibs of Italian origin with mild chronic hemolytic anemia, psychomotor impairment, and undetectable adenylate kinase activity, Bianchi et al. (1999) identified an arg107-to-ter mutation (103000.0002) in the AK1 gene.
Janssen et al. (2000) studied energy homeostasis in muscle of Ak1 null mice. Disruption of Ak1 decreased the potential of myofibers to sustain nucleotide ratios despite upregulated glycolytic, guanylate, and creatine kinase phosphotransfer pathways. Maintained contraction of Ak1-deficient muscles was associated with reduced energy efficiency that was aggravated by hypoxic stress.
Cavalli-Sforza et al. (1979) presented evidence for linkage of transcobalamin II and adenylate kinase (lod score 1.78 at theta 0.139). This was not subsequently confirmed.
In a patient with deletion 9q32-qter secondary to a balanced maternal translocation, Zuffardi et al. (1989) found normal levels of adenylate kinase. Comparing this to previously published data, the authors concluded that the AK1 locus may be situated in 9q32.
In a patient with hemolytic anemia and adenylate kinase deficiency (612631), Matsuura et al. (1989) demonstrated a transition (C-to-T) in exon 6 of the AK1 gene that resulted in an arg-to-trp (CGG-to-TGG) substitution at residue 128 (R128W). Mutant chicken AK1, produced by introducing an arg-to-trp substitution at the same position by oligodeoxynucleotide-directed mutagenesis, showed reduced catalytic activity as well as decreased solubility when expressed in E. coli.
Bianchi et al. (1999) described 2 sibs of Italian origin with mild chronic hemolytic anemia, psychomotor impairment, and undetectable adenylate kinase activity (612631). The other red cell enzyme activities were normal except for a slight decrease in phosphofructokinase (see PFKM; 610681). Both sibs showed increased levels of 2,3-DPG. The parents were not consanguineous and displayed intermediate AK values. The sequence of complete erythrocyte AK1 cDNA in the sibs showed homozygosity for a nonsense mutation at codon 107: CGA (arg) to TGA (stop). The mutation resulted in a truncated protein of 107 amino acids in comparison with the normal 194. Moreover, a 37-bp deletion in the first part of exon 6 (nucleotides 326-362 of the cDNA sequence) was detectable in one allele. Because this deletion was localized after the stop codon, the authors thought that it would not have a further effect on the structure of the enzyme. The new variant was named AK Fidenza, from the origin of the patients.
In an Italian child with hemolytic anemia and undetectable erythrocyte adenylate kinase activity (612631), Qualtieri et al. (1997) identified homozygosity for an A-to-G transition in exon 6 of the AK1 gene, resulting in a tyr164-to-cys (Y164C) substitution. Her parents and brother were heterozygous for the mutation and had 50% normal AK1 activity.
In a Spanish boy with chronic nonspherocytic hemolytic anemia and severe red blood cell adenylate kinase deficiency (612631), Corrons et al. (2003) identified compound heterozygosity for 2 mutations in the AK1 gene: a 118G-A transition resulting in a gly40-to-arg (G40R) substitution, and a 190G-A transition resulting in a gly64-to-arg (G64R) substitution (103000.0005). The boy exhibited a neonatal icterus and splenomegaly and required blood transfusions until the age of 2 years.
For discussion of the gly64-to-arg (G64R) mutation in the AK1 gene that was found in compound heterozygous state in a patient with chronic nonspherocytic hemolytic anemia and severe red blood cell adenylate kinase deficiency (612631) by Corrons et al. (2003), see 103000.0004.
In a white American infant with chronic nonspherocytic hemolytic anemia and severe red blood cell adenylate kinase deficiency (612631), whose parents were first cousins, Corrons et al. (2003) identified homozygosity for an in-frame deletion (GAC) at nucleotide 498 or 501, predicting deletion of either aspartic acid 140 or 141.
In a 3-year-old girl of southern Italian origin with a history of severe hemolytic anemia and low adenylate kinase activity (22% of normal) (612631), Fermo et al. (2004) identified homozygosity for a 1-bp deletion (138delG) in the AK1 gene, causing a frameshift and a premature stop at codon 91.
Allderdice, P. W., Kaita, H., Lewis, M., McAlpine, P. J., Wong, P., Anderson, J., Giblett, E. R. Segregation of marker loci in families with an inherited paracentric insertion of chromosome 9. Am. J. Hum. Genet. 39: 612-617, 1986. [PubMed: 3024483]
Bianchi, P., Zappa, M., Bredi, E., Vercellati, C., Pelissero, G., Barraco, F., Zanella, A. A case of complete adenylate kinase deficiency due to a nonsense mutation in AK-1 gene (arg107-to-stop, CGA-to-TGA) associated with chronic haemolytic anaemia. Brit. J. Haemat. 105: 75-79, 1999. [PubMed: 10233365]
Bowman, J. E., Frischer, H., Ajmar, F., Carson, P. E., Gower, M. K. Population, family and biochemical investigation of human adenylate kinase polymorphism. Nature 214: 1156-1158, 1967. [PubMed: 6053088] [Full Text: https://doi.org/10.1038/2141156a0]
Brock, D. J. H. Evidence against a common subunit in adenylate kinase and pyruvate kinase. Humangenetik 10: 30-34, 1970. [PubMed: 5449947] [Full Text: https://doi.org/10.1007/BF00297637]
Cavalli-Sforza, L. L., King, M. C., Go, R. C. P., Namboodiri, K. K., Lynch, H. T., Wong, L., Kaplan, E. B., Elston, R. C. Possible linkage between transcobalamin II (TC II) and adenylate kinase (AK). (Abstract) Cytogenet. Cell Genet. 25: 140-141, 1979.
Cook, P. J. L., Robson, E. B., Buckton, K. E., Slaughter, C. A., Gray, J. E., Blank, C. E., James, F. E., Ridler, M. A. C., Insley, J., Hulten, M. Segregation of ABO, AK(1) and ACONs in families with abnormalities of chromosome 9. Ann. Hum. Genet. 41: 365-377, 1978. [PubMed: 204246] [Full Text: https://doi.org/10.1111/j.1469-1809.1978.tb01904.x]
Corrons, J.-L. V., Garcia, E., Tusell, J. J., Varughese, K. I., West, C., Beutler, E. Red cell adenylate kinase deficiency: molecular study of 3 new mutations (118G-A, 190G-A, and GAC deletion) associated with hereditary nonspherocytic hemolytic anemia. Blood 102: 353-356, 2003. [PubMed: 12649162] [Full Text: https://doi.org/10.1182/blood-2002-07-2288]
Fenger, K., Sorensen, S. A. Evaluation of a possible sex difference in recombination for the ABO-AK linkage. Am. J. Hum. Genet. 27: 784-788, 1975. [PubMed: 173186]
Ferguson-Smith, M. A., Aitken, D. A., Turleau, C., de Grouchy, J. Localisation of the human ABO: Np-1: AK-1 linkage group by regional assignment of AK-1 to 9q34. Hum. Genet. 34: 35-43, 1976. [PubMed: 184030] [Full Text: https://doi.org/10.1007/BF00284432]
Fermo, E., Bianchi, P., Vercellati, C., Micheli, S., Marcello, A. P., Portaleone, D., Zanella, A. A new variant of adenylate kinase (delG138) associated with severe hemolytic anemia. Blood Cells Molec. Dis. 33: 146-149, 2004. [PubMed: 15315793] [Full Text: https://doi.org/10.1016/j.bcmd.2004.06.002]
Fildes, R. A., Harris, H. Genetically determined variation of adenylate kinase in man. Nature 209: 261-262, 1966. [PubMed: 5915956] [Full Text: https://doi.org/10.1038/209261a0]
Geurts van Kessel, A. H. M., Hagemeijer, A., Westerveld, A., Meera Khan, P., de Groot, P. G., Pearson, P. L. Characterization of chromosomal abnormalities in chronic myeloid leukemia using somatic cell hybrids. (Abstract) Cytogenet. Cell Genet. 32: 280 only, 1982.
Janssen, E., Dzeja, P. P., Oerlemans, F., Simonetti, A. W., Heerschap, A., de Haan, A., Rush, P. S., Terjung, R. R., Wieringa, B., Terzic, A. Adenylate kinase 1 gene deletion disrupts muscle energetic economy despite metabolic rearrangement. EMBO J. 19: 6371-6381, 2000. [PubMed: 11101510] [Full Text: https://doi.org/10.1093/emboj/19.23.6371]
Matsuura, S., Igarashi, M., Tanizawa, Y., Yamada, M., Kishi, F., Kajii, T., Fujii, H., Miwa, S., Sakurai, M., Nakazawa, A. Human adenylate kinase deficiency associated with hemolytic anemia: a single base substitution affecting solubility and catalytic activity of the cytosolic adenylate kinase. J. Biol. Chem. 264: 10148-10155, 1989. [PubMed: 2542324]
Mohandas, T., Sparkes, R. S., Sparkes, M. C., Shulkin, J. D., Toomey, K. E., Funderburk, S. J. Regional localization of human gene loci on chromosome 9: studies of somatic cell hybrids containing human translocations. Am. J. Hum. Genet. 31: 586-600, 1979. [PubMed: 292306]
Povey, S., Slaughter, C. A., Wilson, D. E., Gormley, I. P., Buckton, K. E., Perry, P., Bobrow, M. Evidence for the assignment of loci AK 1, AK 3 and ACON to chromosome 9 in man. Ann. Hum. Genet. 39: 413-422, 1976. [PubMed: 182062] [Full Text: https://doi.org/10.1111/j.1469-1809.1976.tb00145.x]
Qualtieri, A., Pedace, V., Bisconte, M. G., Bria, M., Gulino, B., Andreoli, V., Brancati, C. Severe erythrocyte adenylate kinase deficiency due to homozygous A-to-G substitution at codon 164 of human AK1 gene associated with chronic haemolytic anaemia. Brit. J. Haemat. 99: 770-776, 1997. [PubMed: 9432020] [Full Text: https://doi.org/10.1046/j.1365-2141.1997.4953299.x]
Rapley, S., Robson, E. B., Harris, H., Smith, S. M. Data on the incidence, segregation and linkage relations of the adenylate kinase (AK) polymorphism. Ann. Hum. Genet. 31: 237-242, 1968. [PubMed: 5648746] [Full Text: https://doi.org/10.1111/j.1469-1809.1968.tb00554.x]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Schleutermann, D. A., Bias, W. B., Murdoch, J. L., McKusick, V. A. Linkage of the loci for the nail-patella syndrome and adenylate kinase. Am. J. Hum. Genet. 21: 606-630, 1969. [PubMed: 5365763]
Seger, J., Tchen, P., Feingold, N., Grenand, F., Bois, E. Homozygosity of adenylate kinase allele 3: two cases. Hum. Genet. 43: 337-339, 1978. [PubMed: 212360] [Full Text: https://doi.org/10.1007/BF00278843]
Singer, J. D., Brock, D. J. Half-normal adenylate kinase activity in three generations. Ann. Hum. Genet. 35: 109-114, 1971. [PubMed: 5571743] [Full Text: https://doi.org/10.1111/j.1469-1809.1956.tb01383.x]
Weitkamp, L. R., Sing, C. F., Shreffler, D. C., Guttormsen, S. A. The genetic linkage relations of adenylate kinase: further data on the ABO-AK linkage group. Am. J. Hum. Genet. 21: 600-605, 1969. [PubMed: 5365762]
Westerveld, A., Jongsma, A. P. M., Meera Khan, P., Van Someren, H., Bootsma, D. Assignment of the AK(1): Np: AKO linkage group to human chromosome 9. Proc. Nat. Acad. Sci. 73: 895-899, 1976. [PubMed: 176661] [Full Text: https://doi.org/10.1073/pnas.73.3.895]
Zuffardi, O., Caiulo, A., Maraschio, P., Tupler, R., Bianchi, E., Amisano, P., Beluffi, G., Moratti, R., Liguri, G. Regional assignment of the loci for adenylate kinase to 9q32 and for alpha(1)-acid glycoprotein to 9q31-q32: a locus for Goltz syndrome in region 9q32-qter? Hum. Genet. 82: 17-19, 1989. [PubMed: 2541064] [Full Text: https://doi.org/10.1007/BF00288264]