Article

Diabetologia

, Volume 56, Issue 12, pp 2609-2618

First online:

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

  • Limei LiuAffiliated withDepartment of Endocrinology & Metabolism, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, Shanghai Diabetes Institute Email author 
  • , Kazuaki NagashimaAffiliated withDepartment of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University
  • , Takao YasudaAffiliated withDivision of Cellular and Molecular Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine
  • , Yanjun LiuAffiliated withUCLA School of Medicine, Division of Endocrinology, Charles R. Drew University of Medicine & Sciences
  • , Hai-rong HuAffiliated withState Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University
  • , Guang HeAffiliated withBio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiaotong University
  • , Bo FengAffiliated withDepartment of Endocrinology, Tongji University, The Affiliated East Hospital, Tongji University
  • , Mingming ZhaoAffiliated withDepartment of Endocrinology & Metabolism, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, Shanghai Diabetes Institute
  • , Langen ZhuangAffiliated withDepartment of Endocrinology & Metabolism, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, Shanghai Diabetes Institute
    • , Taishan ZhengAffiliated withDepartment of Endocrinology & Metabolism, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, Shanghai Diabetes Institute
    • , Theodore C. FriedmanAffiliated withUCLA School of Medicine, Division of Endocrinology, Charles R. Drew University of Medicine & Sciences
    • , Kunsan XiangAffiliated withDepartment of Endocrinology & Metabolism, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, Shanghai Diabetes Institute

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Abstract

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.

Keywords

Familial early-onset type 2 diabetes mellitus KCNJ11 Kir6.2 Mutation