Abstract
The glucokinase regulator (GCKR) is a 65-kDa protein that inhibits glucokinase (hexokinase IV) in liver and pancreatic islet. The role of glucokinase (GCK) as pancreatic β cell glucose sensor and the finding of GCK mutations in maturity onset diabetes of the young (MODY) suggest GCKR as a further candidate gene for type 2 diabetes. The inhibition of GCK by GCKR is relieved by the binding of fructose-1-phosphate (F-l-P) to GCKR. F-l-P is the end product of ketohexokinase (KHK, fructokinase), which, like GCK and GCKR, is present in both liver and pancreatic islet. KHK is the first enzyme of the specialized pathway that catabolizes dietary fructose. We have isolated genomic clones containing the human GCKR and KHK genes. By fluorescent in situ hybridization (FISH), KHK maps to Chromosome (Chr) 2p23.2-23.3, a new assignment corroborated by somatic cell hybrid analysis. The localization of GCKR, originally reported by others as 2p22.3, has been reassessed by high-resolution FISH, indicating that, like KHK, GCKR maps to 2p23.2-23.3. The proximity of GCKR and KHK was further demonstrated both by two-color interphase FISH, which suggests that the two genes lie within 500 kb of each other, and by analysis of overlapping YAC and PI clones spanning the interval between GCKR and KHK. A new microsatellite polymorphism was used to place the GCKR-KHK locus between D2S305 and D2S165 on the genetic map. The colocalization of these two metabolically connected genes has implications for the interpretation of linkage or allele association studies in type 2 diabetes. It also raises the possibility of coordinate regulation of GCKR and KHK by common as-acting regulatory elements.
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Bonthron, D.T., Brady, N., Donaldson, I.A., Steinmann, B. (1994). Molecular basis of essential fructosuria; molecular cloning and mutational analysis of human ketohexokinase. Hum. Mol. Genet. 3, 1627–1631.
Collins, J.E., Cole, C.G., Smink, L.J., Garrett, C.L., Leversha, M.A., Soderlund, C.A., Maslen, G.L., Everett, L.A., Rice, K.M., Coffey, A.J., Gregory, S.G., Gwilliam, R., Dunham, A., Davies, A.F., Hassock, S., Todd, C.M., Lehrach, H., Hulsebos, T.J.M., Weissenbach, J., Morrow, B., Kucherlapati, R.S., Wadey, R., Scambler, P.J., Kim, U.-J., Simon, M.I., Peyrard, M., Xie, Y.-G., Carter, N.P., Durbin, R., Dumanski, J.P., Bentley, D.R., and Dunham, I. (1995). A high-density YAC contig map of human chromosome 22. Nature 377 (suppl.), 367–379.
Craig, J.M., Bickmore, W.A. (1994). The distribution of CpG islands on mammalian chromosomes. Nature Genet. 7, 376–382.
Eisner, T.I., Albertsen, H., Gerken, S.C., Cartwright, P., White, R. (1995). Breakpoint analysis: precise localization of genetic markers by means of nonstatistical computation using relatively few genotypes. Am. J. Hum. Genet. 56, 500–507.
Fantes, J.A., Oghene, K., Boyle, S., Danes, S., Fletcher, J.M., Bruford, E.A., Williamson, K., Seawright, A., Schedl, A., Hanson, I., Zehetner, G., Bhogal, R., Lehrach, H., Gregory, S., Williams, J., Little, P.F.R., Sellar, G.C., Hoovers, J., Mannens, M., Weissenbach, J., Junien, C., van Heyningen, V., Bickmore, W.A. (1995). A high-resolution integrated physical, cytogenetic, and genetic map of human chromosome 11: distal pl3 to proximal p15.1. Genomics 25, 447–461.
Francke, U. (1994). Digitised and differentially shaded human chromosome ideograms for genomic applications. Cytogenet. Cell Genet. 65, 206–219.
Gidh-Jain, M., Takeda, J., Xu, L.Z., Lange, A.J., Vionnet, N., Stoffel, M., Froguel, P., Velho, G., Sun, F., Cohen, D., Patel, P., Lo, Y.-M.D., Hattersley, A.T., Luthman, H., Wedell, A., St. Charles, R., Harrison, R.W., Weber, I.T., Bell, G.I., Pilkis, S.J. (1993). Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships. Proc. Natl. Acad. Sci. USA 90, 1932–1936.
Jeggo, P.A., Hafezparast, M., Thompson, A.F., Kaur, G.P., Sandhu, A.K., Athwal, R.S. (1993). A hamster-human subchromosomal hybrid cell panel for chromosome 2. Somatic Cell Mol. Genet. 19, 39–49.
Lehrach, H. (1990). In K.E. Davies, S.M. Tilghman, eds. Genome Analysis, Vol. 1: Genetic and Physical Mapping, (Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press), pp. 39–81.
Malaisse, W.J., Malaisse-Lagae, F., Davies, D.R., Van Schaftingen, E. (1989). Presence of fructokinase in pancreatic islets. FEBS Lett. 255, 175–178.
Malaisse, W.J., Malaisse-Lagae, F., Davies, D.R., Vandercammen, A., Van Schaftingen, E. (1990). Regulation of glucokinase by a fructose-1-phosphate-sensitive protein in pancreatic islets. Eur. J. Biochem. 190, 1539–545.
Prochazka, M., Mochizuki, M., Baier, L.J., Cohen, P.T.W., Bogardus, C. (1995). Molecular and linkage analysis of type-1 protein phosphatase catalytic beta-subunit gene: lack of evidence for its major role in insulin resistance in Pima Indians. Diabetologia 38, 461–466.
Randle, P.J. (1993). Glucokinase and candidate genes for type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 36, 269–275.
Trask, B.J., Massa, H.F., Kenwrick, S., Gitschier, J. (1991). Mapping of human chromosome Xq28 by 2-colour fluorescence in situ hybridisation of DNA sequences to interphase nuclei. Am. J. Hum. Genet. 48, 1–15.
Trask, B.J., Allen, S., Massa, H., Fertita, A., Sachs, R., van den Engh, G., Wu, M. (1993). Studies of metaphase and interphase chromosomes using fluorescence in situ hybridization. Cold Spring Harbor Symp. Quant. Biol. LVIII, 767–775.
Vandercammen, A., Van Schaftingen, E. (1993). Species and tissue distribution of the regulatory protein of glucokinase. Biochem. J. 294, 551–556.
Van Schaftingen, E. (1989). A protein from rat liver confers to glucokinase the property of being antagonistically regulated by fructose 6-phosphate and fructose 1-phosphate. Eur. J. Biochem. 179, 179–184.
Vaxillaire, M., Vionnet, N., Vigouroux, C., Sun, F., Espinosa, R., III, Lebeau, M.M., Stoffel, M., Lehto, M., Beckmann, J.S., Detheux, M., Passa, P., Cohen, D., Van, S.E., Velho, G., Bell, G.I., Froguel, P. (1994). Search for a third susceptibility gene for maturity-onset diabetes of the young: studies with eleven candidate genes. Diabetes 43, 389–395.
Warner, J.P., Leek, J.P., Intody, S., Markham, A.F., Bonthron, D.T. (1995). Human glucokinase regulatory protein (GCKR): cDNA cloning, complete primary structure and chromosomal localization. Mamm. Genome 6, 532–536.
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Hayward, B.E., Fantes, J.A., Warner, J.P. et al. Co-localization of the ketohexokinase and glucokinase regulator genes to a 500-kb region of Chromosome 2p23. Mammalian Genome 7, 454–458 (1996). https://doi.org/10.1007/s003359900132
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DOI: https://doi.org/10.1007/s003359900132