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Identification of Ala2Thr mutation in insulin gene from a Chinese MODY10 family

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Abstract

More than 80% of maturity-onset diabetes of the young (MODY) in Chinese is genetically unexplained. To investigate whether the insulin gene (INS) mutation is responsible for some Chinese MODY, we screened INS mutations causing MODY10 in MODY pedigrees and explored the potential pathogenic mechanisms. INS mutations were screened in 56 MODY familial probands. Structure–function characterization and clinical profiling of identified INS mutations were conducted. An INS mutation, at the position 2 alanine-to-threonine substitution (A2T), was identified and co-segregated with hyperglycemia in a MODY pedigree. The A2T mutation converted an α-helix into a β-sheet at the N-terminal of the signal peptide (SP) of preproinsulin. The A2T mutation did not affect preproinsulin translocation across endoplasmic reticulum (ER) membrane, but impaired its SP cleavage within the ER. In INS-1 cells transfected with an A2T mutant, glucose-stimulated insulin secretion (GSIS) was significantly decreased, while BiP luciferase activities were significantly increased compared to that of wild type (WT). We identified an INS-A2T mutation cosegregating with diabetes in a Chinese MODY pedigree. This mutation severely impaired SP cleavage and thus blocked the formation of proinsulin, resulting in enhanced ER stress, which may be responsible for decreased insulin secretion and subsequently, the onset of MODY10.

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Abbreviations

MODY:

Maturity-onset diabetes of the young

INS :

Insulin gene

SP:

Signal peptide

ER:

Endoplasmic reticulum

GSIS:

Glucose-stimulated insulin secretion

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Acknowledgements

We thank Lin He for his assistance. We apologize to many authors whose works could not be cited due to space limitations. This work is supported by the National Natural Science Foundation of China [Grant Numbers 81970686, 81770791, 81471012, 81270876], the Interdisciplinary Program of Shanghai Jiao Tong University [Grant Number YG2019ZDA08], the Shanghai Leading Talent [Grant Number SLJ15055], and the National Institute of Diabetes and Digestive and Kidney Diseases [Grant Number SC1DK104821 to Y. Liu].

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Author notes

  1. Juan Zhang, Yanjun Liu, Ming Li are Co-first authors and contributed equally to this work.

Authors and Affiliations

  1. Shanghai Diabetes Institute, Department of Endocrinology & Metabolism, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, 600 Yishan Road, Shanghai, 200233, China

    Juan Zhang, Ming Li, Rong Zhang, Yating Chen, Jun Yin & Limei Liu

  2. Department of Internal Medicine, Charles R. Drew University, Los Angeles, USA

    Yanjun Liu

  3. David Geffen School of Medicine at University of California, Los Angeles, USA

    Yanjun Liu

  4. Department of Endocrinology, School of Medicine, Shanghai Tongren Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China

    Xiaoxu Ge

  5. Department of Pediatrics, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA

    Ying Wang

  6. School of Medicine, Magee-Womens Research Institute, University of Pittsburgh, 204 Craft Ave., Pittsburgh, PA, 15213, USA

    Xin Huang

  7. Department of Nutritional Science and Toxicology, University of California at Berkeley, Berkeley, USA

    Di Yang

  8. Department of Endocrinology & Metabolism, Putuo Hospital Attached to Shanghai University of Traditional Chinese Medicine, 164 Lanxi Road, Shanghai, 200000, China

    Ming Lu

  9. Department of Endocrinology, Weihai Municipal Hospital, No. 70, Heping Road, Weihai, 264200, China

    Mingqiang Song

  10. Department of Endocrinology, Xianxian Hospital of Traditional Chinese Medicine, Cangzhou City, Hebei Province, China

    Yongfeng Wang

  11. School of Population Health and Environmental Science, King’s College London, London, UK

    Yanzhong Wang

  12. Department of Nephrology, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, 600 Yishan Road, Shanghai, 200233, China

    Feng Wang

  13. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA

    Meisheng Jiang

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  1. Juan Zhang
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Correspondence to Limei Liu.

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Zhang, J., Liu, Y., Li, M. et al. Identification of Ala2Thr mutation in insulin gene from a Chinese MODY10 family. Mol Cell Biochem 470, 77–86 (2020). https://doi.org/10.1007/s11010-020-03748-0

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