【摘要】 目的 :探索包含青年发病的成年型糖尿病 ( maturity- onset diabetes of the young,MODY)患者的 2型糖尿病家族中可能存在的 MODY基因的致病突变。方法 :选择 MODY基因中突变率最高的葡萄糖激酶 ( glucokinase,GCK,MODY2 )和肝细胞核因子- 1α( hepatic nuclear factor- 1α,HNF- 1α,MODY3 )基因的微卫星多态遗传标志 ,在一个包含 2名 MODY患者的中国人 2型糖尿病家系中进行连锁分析 ,对可能与疾病连锁的基因进行全基因外显子的突变筛查—— DNA序列直接测定以明确具体的碱基突变和所编码的氨基酸的改变。结果 :家系 5 0 0 0 1中 MODY3的最大 L OD( logarithm of odds)值达到 2 .3 75 93 0 (θ=0 .0 0 0 0 0 0 ) ,但未发现与MODY2连锁的依据。 DNA直接测序发现在家系 5 0 0 0 1中所有家族成员 MODY3基因外显子 7中存在一个杂合多态 Ser4 87Asn( AGC/ AAC) ,该多态在正常人中也可见到。结论 :GCK基因内或附近的基因变异不是本家系 2型糖尿病的主要致病原因 ;HNF- 1α基因的启动子和所有外显子内均未发现明确的致病突变 ,但无法否定内含子或其他调节区域的变异有可能的致病倾向 ;也不能排除HNF- 1α基因附近其他未知疾病基因的致病可能。本家系的致病基因有待进一步明确。更多还原

【Abstract】 Objective:To explore the GCK and HNF 1α gene muta ti on(s) in a type 2 diabetes (non insulin dependent diabetes mellitus, NIDDM) fam ily containing subjects with maturity onset diabetes of the young (MODY). Methods:The microsatellite polymorphism genetic markers of glucokinase (GCK, MODY2) and hepatocyte nuclear factor 1α (HNF 1α, MODY3) genes were selected to perform the classical linkage analysis in the NIDDM/MODY family 50001. Direct sequencing was employed to confirm the variation of nucleotide(s) in the promot er and all the exons of HNF 1α gene.Results:No linkage was found in GCK genetic marker with diabetes in family 50001. The maximal LOD(logarithm of o dds) score was 2.375 930(θ=0.000 000) for the HNF 1α genetic marker with diab ete s at the mode of autosomal dominant in family 50001. By direct sequencing, a het erozygous polymorphism, Ser487 Asn(AGC/AAC), was indicated in exon 7, and it cou ld be found in the diabetic and normal subjects as well. Conclusion:Th ere is no enough evidence to demonstrate that the variation in or near GCK gene is the major cause of diabetes in the family. Although no definite mutations wer e found in the promoter and all the exons of HNF 1α gene, it could not be nega ted that the variation in the introns or other regulating regions may predispose to this disease in pedigree 50001. We could not exclude the possibility that ot her gene mutation near this locus might cause this familial disorder, for the ma ximal linkage LOD score of D12S86 reached 2.375 930(θ=0.000 000), which is clos ed to 3 0. The mutation related to diabetes in this family needs further invest igation.更多还原