Diabetologia

, Volume 56, Issue 12, pp 2609–2618

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

  • Limei Liu
  • Kazuaki Nagashima
  • Takao Yasuda
  • Yanjun Liu
  • Hai-rong Hu
  • Guang He
  • Bo Feng
  • Mingming Zhao
  • Langen Zhuang
  • Taishan Zheng
  • Theodore C. Friedman
  • Kunsan Xiang
Article

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 

Abbreviations

HI

Hyperinsulinism

IA-2

Tyrosine phosphatase-like protein

IGT

Impaired glucose tolerance

KATP

ATP-sensitive potassium channel

MODY

Maturity-onset diabetes of the young

PNDM

Permanent neonatal diabetes

SNP

Single nucleotide polymorphism

TM

Transmembrane

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • 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. 1.Department of Endocrinology & Metabolism, Shanghai Jiaotong University Affiliated Sixth People’s HospitalShanghai Diabetes InstituteShanghaiChina
  2. 2.Department of Diabetes and Clinical Nutrition, Graduate School of MedicineKyoto UniversityKyotoJapan
  3. 3.Division of Cellular and Molecular Medicine, Department of Physiology and Cell BiologyKobe University Graduate School of MedicineKobeJapan
  4. 4.UCLA School of Medicine, Division of EndocrinologyCharles R. Drew University of Medicine & SciencesLos AngelesUSA
  5. 5.State Key Laboratory of Genetic Engineering, School of Life SciencesFudan UniversityShanghaiChina
  6. 6.Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education)Shanghai Jiaotong UniversityShanghaiChina
  7. 7.Department of Endocrinology, Tongji UniversityThe Affiliated East Hospital, Tongji UniversityShanghaiChina

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