维吾尔族早发糖尿病家系中MODY1-6基因缺陷的分子筛查

Molecular Sequencing of MODY1-6 Genes in Uighur Early-onset Diabetes Pedigree

探讨MODY1-6(HNF4α,GCK,HNF1α,IPF1,HNF1β,NEUROD1)基因是否为一个疑为MODY的维吾尔族早发糖尿病家系的主要致病基因。研究收集新疆喀什地区维吾尔族4代健在的MODY家系一个,抽提两个家系成员的基因组DNA,PCR扩增HNF4α,GCK,HNF1α,IPF1,HNF1β,NEUROD1基因的所有外显子和外显子与内含子拼接区,将PCR产物纯化直接双向测序。结果表明,未发现MODY1-6基因致病突变,但发现了17种多态性变异。HNF1α基因的同义突变Gln497Gln和NEUROD1基因的c.164G>A国内外未见报道,其他都是已报道的MODY基因常见多态性。由此得出,MODY1-6基因的变异不是该维吾尔族MODY家系的主要致病基因。MODY基因突变存在种族异质性,为进一步研究维吾尔族MODY家系分子基础提供了重要的依据。所筛查到MODY基因多态性可能增加了家系内成员糖尿病的易感性,具体机制有待进一步研究。

Maturity-Onset Diabetes of the Young（MODY） is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance,early age of onset,and pancreatic beta cell dysfunction.Six MODY genes represent an excellent candidate gene set for identification genetic variation in the MODY family.There is no prior study on the molecular genetics of early-onset type II diabetes in Xinjiang Uighur Autonomous Region and also there is no report on mutations in MODY genes in Uighur ethnic population.The screening for mutations and polymorphism in six known MODY genes（HNF4α,GCK,HNF1α,IPF1,HNF1β,and NEUROD1） in a Uighur family with clinically diagnosed with MODY are studied.One Uighur MODY family from Kashgar City of Xinjiang was involved in this research with its informed consents.Proband and his father were screened for mutations and polymorphism in exon and exon-intron boundaries of six known MODY genes by PCR method followed by direct DNA sequencing.All sequences were analyzed and compared with the reference sequence from NCBI with the Lasergene software（DNASTAR）.Seventeen sequence variations are identified and none of them are classified as the pathogenic mutation.Sequence variants of HNF1α gene are relatively more common.HNF1α Exon7 p.Gln497Gln,and NEUROD1 Exon1 c.164GA are novel variations.Others are all previously described common polymorphisms.No pathogenic mutations or polymorphisms found in GCK.In summary,it is the first report in which six known MODY genes are screened for mutations in Uighur ethnic group.Mutations in MODY1-6 genes might not be the cause of this MODY family.The negative results in MODY genes are provided a further support for the high heterogeneity of this disease.This is the first step for the researches on the MODY genes in Uighur MODY family.The variations which are identified in the study might indicate a relatively high susceptibility to MODY or Type II DM for the Uighur population.