Mutations in KCNJ11 are associated with the development of autosomal dominant, early-onset type 2 diabetes.
Mutations in KCNJ11 are associated with the development of autosomal dominant, early-onset type 2 diabetes.
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KCNJ11 突变与常染色体显性早发 2 型糖尿病的发生有关
DOI：
10.1007/s00125-013-3031-9
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发表时间：
2013-12
期刊：
影响因子：
8.2
通讯作者：
Xiang K
中科院分区：
文献类型：
--
作者：
Liu L;Nagashima K;Yasuda T;Liu Y;Hu HR;He G;Feng B;Zhao M;Zhuang L;Zheng T;Friedman TC;Xiang K
目的/假设超过90%的中国家族性早发性2型糖尿病是遗传原因不明的。方法对96例家族性早发性2型糖尿病先证者及其家系进行KCNJ11基因突变筛查。结果在3个早发性2型糖尿病家系中发现了3个新的KCNJ11突变：R27H、R192H和S116F117del。R27H或R192H突变的KCNJ11可显著降低ATP敏感性(E23K>；R27H>；C42R>；R192H>；R201H)，但在功能缺失的S116F117del通道上未检测到ATP敏感性钾通道电流。分子模拟表明，R192H对通道ATP结合口袋的影响大于R27H，这可能定性地解释了为什么R192H突变的ATP敏感性比R27H低7倍。S116F117del通道的形状可能被压缩，这可以解释为什么突变的通道没有电流。对R27H或R192H携带者停用胰岛素，对R27H或R192H携带者实施磺脲类药物治疗，对S116F117del携带者继续/转而使用胰岛素治疗，可获得良好的血糖控制。结论/解释我们的结果提示，对家族性早发性2型糖尿病KCNJ11突变的基因诊断可能有助于了解分子病因，并为中国和亚洲其他地区的糖尿病患者提供更个性化的治疗。
Aims/hypothesisMore than 90% of Chinese familial early-onset type 2 diabetes mellitus is genetically unexplained. To investigate the molecular aetiology, we identified and characterised whether mutations in the KCNJ11 gene are responsible for these families.MethodsKCNJ11 mutations were screened for 96 familial early-onset type 2 diabetic probands and their families. Functional significance of the identified mutations was confirmed by physiological analysis, molecular modelling and population survey.ResultsThree novel KCNJ11 mutations, R27H, R192H and S116F117del, were identified in three families with early-onset type 2 diabetes mellitus. Mutated KCNJ11 with R27H or R192H markedly reduced ATP sensitivity (E23K>R27H>C42R>R192H>R201H), but no ATP-sensitive potassium channel currents were detected in the loss-of-function S116F117del channel in vitro. Molecular modelling indicated that R192H had a larger effect on the channel ATP-binding pocket than R27H, which may qualitatively explain why the ATP sensitivity of the R192H mutation is seven times less than R27H. The shape of the S116F117del channel may be compressed, which may explain why the mutated channel had no currents. Discontinuation of insulin and implementation of sulfonylureas for R27H or R192H carriers and continuation/switch to insulin therapy for S116F117del carriers resulted in good glycaemic control.Conclusions/interpretationOur results suggest that genetic diagnosis for the KCNJ11 mutations in familial early-onset type 2 diabetes mellitus may help in understanding the molecular aetiology and in providing more personalised treatment for these specific forms of diabetes in Chinese and other Asian patients.