Hayward B E, Fantes J A, Warner J P, Intody S, Leek J P, Markham A F, Bonthron D T
Human Genetics Unit, University of Edinburgh, Western General Hospital, UK.
Mamm Genome. 1996 Jun;7(6):454-8. doi: 10.1007/s003359900132.
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 beta 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-1-P) to GCKR. F-1-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 P1 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 cis-acting regulatory elements.
葡萄糖激酶调节蛋白（GCKR）是一种65 kDa的蛋白质，可抑制肝脏和胰岛中的葡萄糖激酶（己糖激酶IV）。葡萄糖激酶（GCK）作为胰腺β细胞葡萄糖传感器的作用以及在青年发病的成年型糖尿病（MODY）中发现GCK突变表明，GCKR是2型糖尿病的另一个候选基因。果糖-1-磷酸（F-1-P）与GCKR结合可解除GCKR对GCK的抑制作用。F-1-P是酮己糖激酶（KHK，果糖激酶）的终产物，与GCK和GCKR一样，KHK也存在于肝脏和胰岛中。KHK是分解膳食果糖的特殊途径的第一个酶。我们分离出了包含人类GCKR和KHK基因的基因组克隆。通过荧光原位杂交（FISH），KHK定位于染色体（Chr）2p23.2 - 23.3，体细胞杂交分析证实了这一新定位。最初其他人报道GCKR定位于2p22.3，通过高分辨率FISH对其定位进行了重新评估，结果表明，与KHK一样，GCKR也定位于2p23.2 - 23.3。双色间期FISH进一步证明了GCKR和KHK的邻近性，这表明这两个基因彼此相距在500 kb以内，同时对跨越GCKR和KHK之间区间的重叠酵母人工染色体（YAC）和P1克隆进行分析也证明了这一点。一种新的微卫星多态性被用于将GCKR - KHK基因座定位在遗传图谱上的D2S305和D2S165之间。这两个代谢相关基因的共定位对2型糖尿病连锁或等位基因关联研究的解释具有重要意义。这也增加了通过共同的顺式作用调控元件对GCKR和KHK进行协同调控的可能性。
