Objective: To explore the relationship between the insulin resistance and thedefects or mutations or mutations in insulin receptor (InsR)gene. Methods: Using the single-strandconformation polymorphism(SSCP), mutations and polymorphisms were detected in nine patients withacan-thosis nigricans (AN) and their first degree relatives in exon 17 and 20 of InsR gene. Thepolymorphisms and mutations were confirmed by DNA direct sequencing. Results: Fourteen variant SSCPpat-terns were detected. Direct sequencing revealed seven point mutations and six silentpolymorphisms. Five of the mutations appeared not to be mentioned in the previous literature. Thesemutations were all located within the domain of tyrokinase in InsR. Conclusion: It seem to us thatalmost all the AN patients with severe insulin resistance in this study have mutations in InsRtyrokinase domain.
目的 探索包含青少年起病的成人型糖尿病(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(GCK,MODY2)和肝细胞核因子1α(HNF-1α,MODY3)基因的微卫星多态遗传标志在2个包含临床MODY患者的中国人2型糖尿病家系中进行连锁分析,对HNF-1α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核苷酸突变和所编码的氨基酸的改变。结果 HNF-1α基因标志物在家系50001中MODY3的最大LOD值达到2.38(θ=0.00),家系50002中,MODY3最大LOD值达到3.59(θ=0.00);两家系均未发现与MODY2连锁的依据。DNA直接测序发现在家系50001中所有家族成员外显子7中存在一个杂合多态Ser487Asn(AGC/AAC),该多态在正常人中也可见到;家系50002中NIDDM/MODY个体MODY3基因外显子5编码区存在一个杂合错义突变Tyr322Asn(TAT→AAT)。结论 GCK基因内或附近的基因变异不是本家系糖尿病的主要致病原因;家系50001中,HNF-1α基因的启动子和所有外显子内没有发现明确的致病突变,但不能否定内含子或其他调节区域的变异可能的致病倾向;由于本家系遗传标志D12S86与糖尿病的连锁LOD最大值达到2.38(θ=0.00),所以也不能排除HNF-1α基因附近其他未知?
