Alternative titles; symbols
HGNC Approved Gene Symbol: CKM
Cytogenetic location: 19q13.32 Genomic coordinates (GRCh38): 19:45,306,413-45,322,875 (from NCBI)
Creatine kinase (CK; EC 2.7.3.2) catalyzes the reversible transfer of a phosphate from phosphocreatine to adenosine diphosphate, generating adenosine triphosphate in tissues such as brain and muscle that require large amounts of an energy source. The active form of the cytosolic enzyme is a dimer of 2 subunit types, CKM and CKB (123280), which can combine to form 3 electrophoretically separable isozymes, CKMM, CKBB, and CKMB (summary by Nigro et al., 1987). The dimeric creatine kinase isozymes are involved in maintaining intracellular ATP levels, particularly in tissues that have high energy demands. The creatine kinase MM isozyme is found exclusively in striated muscle; the BB isozyme is found in smooth muscle, brain, and nerve; CKMB is found in human heart (summary by Perryman et al., 1986).
Dawson et al. (1968) determined that creatine kinase exists as a dimer: the muscle enzyme (MM) consists of 2 identical M subunits, and the brain enzyme (BB) consists of 2 identical B subunits. Other tissues showed a third, hybrid MB enzyme. Schweinfest et al. (1985) used a chicken CK-M cDNA clone to isolate a human clone from a cDNA library constructed from human heart mRNA. One clone showed greater than 90% homology to rabbit CK-M and less than 50% homology to rabbit CK-B, indicating that it represented the human CK-M gene.
By somatic cell hybrid analysis, Schweinfest et al. (1985) mapped the human CKM gene to chromosome 19.
By in situ hybridization, Nigro et al. (1987) regionalized the assignment of CKM to 19q13. On the basis of high-resolution g-banding, the predominant labeling site was 19q13.2-q13.3.
By Southern analysis of hybrid cell DNA, Stallings et al. (1988) confirmed the assignment of CKM to chromosome 19. Study of independent hybrids that had portions of 19q missing indicated that APOC2 (608083) is distal to CKM.
Studying DNAs from somatic cell hybrids with a rearranged 19q that carries a breakpoint across the CKM gene, Smeets et al. (1990) localized the CKM gene and the 2 DNA repair genes, ERCC1 (126380) and ERCC2 (126340), within the same 250 kb of DNA. The order appeared to be cen--CKM--ERCC2--ERCC1--ter, with APOC2 (608083) being at a distance more than 260 kb proximal to CKM. The transcriptional start sites of the CKM and DNA-repair genes are all on the telomeric side of the genes.
In 59 families with myotonic dystrophy (DM; 160900) from Italy and Spain, Gennarelli et al. (1991) found very close linkage of the disease to a polymorphism at the CKMM locus; maximum lod score = 21.26 at theta = 0.00. Bailly et al. (1991) sequenced CKMM cDNA from a DM chromosome 19 and found 2 novel polymorphisms but no translationally significant mutations. They concluded that this finding excludes the CKMM gene as the site of mutation in DM.
Steeghs et al. (1997) generated mice who had combined deficiency of cytosolic CK (CKM) and mitochondrial CK (CKMT; 123290). This mutation blocked creatine kinase-mediated phosphocreatine (PCr)-to-ATP transphosphorylation in skeletal muscle. Contrary to expectation, the PCr level was only marginally affected, but the compound was rendered metabolically inert. Mutant muscles in vivo showed significantly impaired tetanic force output, increased relaxation times, altered mitochondrial volume and location, and conspicuous tubular aggregates of sarcoplasmic reticulum membranes, as seen in myopathies with electrolyte disturbances. In depolarized myotubes cultured in vitro, CK absence influenced both the release and sequestration of calcium ion. The data pointed to a direct link between the CK-PCr system and the regulation of calcium ion flux during the excitation and relaxation phases of muscle contraction.
Bailly, J., MacKenzie, A. E., Leblond, S., Korneluk, R. G. Assessment of a creatine kinase isoform M defect as a cause of myotonic dystrophy and the characterization of two novel CKMM polymorphisms. Hum. Genet. 86: 457-462, 1991. [PubMed: 2016086] [Full Text: https://doi.org/10.1007/BF00194633]
Dawson, D. M., Eppenberger, H. M., Eppenberger, M. E. Multiple molecular forms of creatine kinases. Ann. N.Y. Acad. Sci. 151: 616-626, 1968. [PubMed: 5251888] [Full Text: https://doi.org/10.1111/j.1749-6632.1968.tb11922.x]
Gennarelli, M., Novelli, G., Cobo, A., Baiget, M., Dallapiccola, B. 3-Prime creatine kinase (M-type) polymorphisms linked to myotonic dystrophy in Italian and Spanish populations. Hum. Genet. 87: 654-656, 1991. [PubMed: 1682233] [Full Text: https://doi.org/10.1007/BF00201719]
Nigro, J. M., Schweinfest, C. W., Rajkovic, A., Pavlovic, J., Jamal, S., Dottin, R. P., Hart, J. T., Kamarck, M. E., Rae, P. M. M., Carty, M. D., Martin-DeLeon, P. cDNA cloning and mapping of the human creatine kinase M gene to 19q13. Am. J. Hum. Genet. 40: 115-125, 1987. [PubMed: 3031982]
Perryman, M. B., Kerner, S. A., Bohlmeyer, T. J., Roberts, R. Isolation and sequence analysis of a full-length cDNA for human M creatine kinase. Biochem. Biophys. Res. Commun. 140: 981-989, 1986. [PubMed: 3778496] [Full Text: https://doi.org/10.1016/0006-291x(86)90732-1]
Roman, D., Billadello, J., Gordon, J., Grace, A., Sobel, B., Strauss, A. Complete nucleotide sequence of dog heart creatine kinase mRNA: conservation of amino acid sequence within and among species. Proc. Nat. Acad. Sci. 82: 8394-8398, 1985. [PubMed: 3866230] [Full Text: https://doi.org/10.1073/pnas.82.24.8394]
Rosenberg, U. B., Kunz, G., Frischauf, A., Lehrach, H., Mahr, R., Eppenberger, H. M., Perriard, J.-C. Molecular cloning and expression during myogenesis of sequences coding for M-creatine kinase. Proc. Nat. Acad. Sci. 79: 6589-6592, 1982. [PubMed: 6959139] [Full Text: https://doi.org/10.1073/pnas.79.21.6589]
Schweinfest, C. W., Nigro, J. M., Rajkovic, A., Dottin, R. P., Hart, J. M., Karmack, M. E., Rae, P. M. M. Localization of the human creatine kinase-M gene to chromosome 19. (Abstract) Cytogenet. Cell Genet. 40: 740-741, 1985.
Smeets, H., Bachinski, L., Coerwinkel, M., Schepens, J., Hoeijmakers, J., van Duin, M., Grzeschik, K.-H., Weber, C. A., de Jong, P., Siciliano, M. J., Wieringa, B. A long-range restriction map of the human chromosome 19q13 region: close physical linkage between CKMM and the ERCC1 and ERCC2 genes. Am. J. Hum. Genet. 46: 492-501, 1990. [PubMed: 2309701]
Stallings, R. L., Olson, E., Strauss, A. W., Thompson, L. H., Bachinski, L. L., Siciliano, M. J. Human creatine kinase genes on chromosomes 15 and 19, and proximity of the gene for the muscle form to the genes for apolipoprotein C2 and excision repair. Am. J. Hum. Genet. 43: 144-151, 1988. [PubMed: 3400641]
Steeghs, K., Benders, A., Oerlemans, F., de Haan, A., Heerschap, A., Ruitenbeek, W., Jost, C., van Deursen, J., Perryman, B., Pette, D., Bruckwilder, M., Koudijs, J., Jap, P., Veerkamp, J., Wieringa, B. Altered Ca(2+) responses in muscles with combined mitochondrial and cytosolic creatine kinase deficiencies. Cell 89: 93-103, 1997. [PubMed: 9094718] [Full Text: https://doi.org/10.1016/s0092-8674(00)80186-5]
Watts, D. C. Creatine kinase (adenosine 5-prime-triphosphate-creatine phosphotransferase).In: Boyer, P. D. (ed.) : The Enzymes. Vol. 8. (3rd ed.) New York: Academic Press (pub.) 1973. Pp. 384-455.