Mutations in KCNJ11 are associated with the development of autosomal dominant, early-onset type 2 diabetes

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• 作者：Limei Liu (1)
  Kazuaki Nagashima (2)
  Takao Yasuda (3)
  Yanjun Liu (4)
  Hai-rong Hu (5)
  Guang He (6)
  Bo Feng (7)
  Mingming Zhao (1)
  Langen Zhuang (1)
  Taishan Zheng (1)
  Theodore C. Friedman (4)
  Kunsan Xiang (1)
  
• 关键词：Familial early ; onset type 2 diabetes mellitus ; KCNJ11 ; Kir6.2 ; Mutation
• 刊名：Diabetologia
• 出版年：2013
• 出版时间：December 2013
• 年：2013
• 卷：56
• 期：12
• 页码：2609-2618
• 全文大小：
• 作者单位：Limei Liu (1)
  Kazuaki Nagashima (2)
  Takao Yasuda (3)
  Yanjun Liu (4)
  Hai-rong Hu (5)
  Guang He (6)
  Bo Feng (7)
  Mingming Zhao (1)
  Langen Zhuang (1)
  Taishan Zheng (1)
  Theodore C. Friedman (4)
  Kunsan Xiang (1)
  
  1. Department of Endocrinology & Metabolism, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, Shanghai Diabetes Institute, 600 Yishan Road, Shanghai, 200233, China
  2. Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
  3. Division of Cellular and Molecular Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan
  4. UCLA School of Medicine, Division of Endocrinology, Charles R. Drew University of Medicine & Sciences, Los Angeles, CA, USA
  5. State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
  6. Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiaotong University, Shanghai, China
  7. Department of Endocrinology, Tongji University, The Affiliated East Hospital, Tongji University, Shanghai, China
  
• ISSN：1432-0428

文摘

Aims/hypothesis More 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. Methods KCNJ11 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. Results Three 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/interpretation Our 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.