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

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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.

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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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Acknowledgements

We thank Susumu Seino and Tadao Shibasaki (Division of Cellular and Molecular Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Japan), Nobuya Inagaki (Department of Diabetes and Clinical Nutrition, Kyoto University, Japan) and Long Yu (State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, China) for their cooperation. We also thank Weiping Jia, Xiaojing Ma, Ming Lu, Can Li, Weijing Zhao, Rong Zhang, Jun Yin, Yuqian Bao and Jing Xu (Shanghai Diabetes Institute, Department of Endocrinology & Metabolism, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, Shanghai, China) for their technical support and cooperation.

Funding

This research was supported by grants from the Project of National Natural Science Foundation of China (nos. 81270876, 30771022 and 30971384) and the Shanghai Scientific & Technical Committee Foundation (nos. 10XD1403400 and 06ZR14051). YL is supported by NIH grant SC1DK087655.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

All authors contributed to the conception and design, or analysis and interpretation of data, drafted the article or revised it critically for important intellectual content, and approved the final version to be published.

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Authors and Affiliations

  1. Department of Endocrinology & Metabolism, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, Shanghai Diabetes Institute, 600 Yishan Road, Shanghai, 200233, China

    Limei Liu, Mingming Zhao, Langen Zhuang, Taishan Zheng & Kunsan Xiang

  2. Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Kazuaki Nagashima

  3. Division of Cellular and Molecular Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan

    Takao Yasuda

  4. UCLA School of Medicine, Division of Endocrinology, Charles R. Drew University of Medicine & Sciences, Los Angeles, CA, USA

    Yanjun Liu & Theodore C. Friedman

  5. State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China

    Hai-rong Hu

  6. Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiaotong University, Shanghai, China

    Guang He

  7. Department of Endocrinology, Tongji University, The Affiliated East Hospital, Tongji University, Shanghai, China

    Bo Feng

Authors
  1. Limei Liu
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  2. Kazuaki Nagashima
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  3. Takao Yasuda
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  4. Yanjun Liu
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  6. Guang He
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  7. Bo Feng
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  8. Mingming Zhao
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  9. Langen Zhuang
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  10. Taishan Zheng
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  11. Theodore C. Friedman
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  12. Kunsan Xiang
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Corresponding author

Correspondence to Limei Liu.

Additional information

Limei Liu, Kazuaki Nagashima, Takao Yasuda, Yanjun Liu, Hai-rong Hu and Guang He contributed equally to this study.

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Liu, L., Nagashima, K., Yasuda, T. et al. Mutations in KCNJ11 are associated with the development of autosomal dominant, early-onset type 2 diabetes. Diabetologia 56, 2609–2618 (2013). https://doi.org/10.1007/s00125-013-3031-9

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  • DOI: https://doi.org/10.1007/s00125-013-3031-9

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