中国人早发及多发糖尿病人群中葡萄糖激酶基因筛查及1个新的错义突变V5L的发现

Identification of one novel mutation V5L in the GCK gene in Chinese early-onset and/or multiplex diabetes pedigrees

目的葡萄糖激酶(GCK)基因突变是白种人青年发病的成年型糖尿病(MODY)的常见原因。本研究对中国人早发及多发糖尿病人群进行GCK基因筛查,以了解该基因突变和序列变异在中国人早发糖尿病人群中的发生情况。方法应用对PCR产物进行直接测序的方法,在341名无亲缘关系的中国人(其中80名为正常对照者,261例为早发和/或多发糖尿病家系先证者)中对GCK基因启动子区、整个编码区及内含子/外显子结合区进行筛查。结果 (1)在1个多发糖尿病家系中发现1个新的GCK基因突变V5L(c.13G→C),该突变位于肝脏特异性转录的GCK基因的外显子1b处,且在该家系中表现为与糖尿病共分离,正常对照者中未发现该突变。(2)发现几种先前已报道的序列变异:-84bp(C→G),IVS1b+12(A→T),IVS5+29(G→T),IVS9+8(T→C)及IVS9+49(G→A)。结论新发现1个可能与糖尿病发病相关的MODY2基因(GCK)突变(V5L),GCK基因突变可能不是中国人早发及多发糖尿病的主要原因。

Objective Mutations in the glucokinase gene cause the type 2 form of maturity-onset diabetes of the young （MODY2）. The aim of this study was to determine the prevalence of mutations and sequences variations of GCK gene in Chinese with familial early-onset and/or multiplex diabetes mellitus. Methods Screened were all ten exons of the GCK gene, including exon/intron junctions, by direct sequencing in 341 unrelated Chinese subjects comprising 80 healthy controls and 261 probands of earlyonset and/or multiplex diabetes pedigrees. Results We identified one novel mutation V5L （c. 13G→C） in the GCK gene in one multiplex diabetes pedigree. This mutation located in exon lb,and the exon lb is specific to the liver transcripts, which encodes the major isoform expressed in liver, and co-segregated with diabetes in pedigree. And the mutation was not identified in controls. Moreover, we identified several variants which were reported previously： 5＇-untranslated region of exon la, 84bp upstream of the translation initiation site-84bp（C→G） ; IVSlb＋12 （A→T） ; IVS 5＋29 （G→T） ; IVS 9＋8 （T→C） and IVS 9＋49 （G→A）. Conclusions Identification of one novel mutation V5L in the GCK gene in Chinese early-onset and/or multiplex diabetes pedigrees. GCK gene may be a rare cause of early-onset and/or multiplex diabetes among Chinese patients.