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Clinical and functional characterization of a novel KCNJ11 (c.101G > A, p.R34H) mutation associated with maturity-onset diabetes mellitus of the young type 13

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Abstract

Purpose

This study aimed to describe the clinical features, diagnostic and therapeutic course of a patient with MODY13 caused by KCNJ11 (c.101G > A, p.R34H) and how it contributes to the pathogenesis of MODY13, and to explore new therapeutic targets.

Methods

Whole-exome sequencing was used to screen prediagnosed individuals and family members with clinically suspected KCNJ11 mutations. Real-time fluorescence quantitative PCR, western blotting, thallium flux of potassium channels, glucose-stimulated insulin secretion (GSIS), and immunofluorescence assays were used to analyze the regulation of insulin secretion by the KCNJ11 mutant in MIN6 cells. Daily blood glucose levels were continuously monitored for 14 days in the proband using the ambulatory blood glucose meter (SIBIONICS).

Results

Mutation screening of the entire exon of the gene identified a heterozygous KCNJ11 (c.101G > A, p.R34H) mutation in the proband and his mother. Cell-based GSIS assays after transfection of MIN6 using wild-type and mutant plasmids revealed that this mutation impaired insulin secretory function. Furthermore, we found that this impaired secretory function is associated with reduced functional activity of the mutant KCNJ11 protein and reduced expression of the insulin secretion-associated exocytosis proteins STXBP1 and SNAP25.

Conclusion

For the first time, we revealed the pathogenic mechanism of KCNJ11 (c.101G > A, p.R34H) associated with MODY13. This mutant can cause alterations in KATP channel activity, reduce sensitivity to glucose stimulation, and impair pancreatic β-cell secretory function by downregulating insulin secretion-associated exocytosis proteins. Therefore, oral sulfonylurea drugs can lower blood glucose levels through pro-insulinotropic effects and are more favorable for patients with this mutation.

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Abbreviations

ACMG:

American College of Medical Genetics

ALT:

albumin transaminase

AST:

aspartate transaminase

BMI:

body mass index

FBG:

fasting blood glucose

FCP:

fasting serum C-peptide

FINS:

fasting serum insulin

GSIS:

glucose stimulated insulin secretion

HbA1c:

hemoglobin A1C

HDL:

high density lipoprotein

KATP:

ATP-sensitive potassium channel

KCNJ11:

potassium inwardly-rectifying channel subfamily J member 11

LDL:

low density lipoprotein

MODY:

maturity-onset diabetes of the young

MODY13:

maturity-onset diabetes mellitus of the young type 13

SNAP25:

synaptosome associated protein 25

STXBP1:

syntaxin binding protein 1

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Acknowledgements

We thank the Endocrine Laboratory of Qilu Hospital, Shandong University for technical support, all authors for their help during clinical data collection and experiments.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 82270845), Double First Class University Plan (Grant No. 26010162914001), and the Major Basic Research Project of Natural Science Foundation of Shandong Province (Grant No. ZR2020ZD15).

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Authors and Affiliations

  1. Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China

    Xiaoyu Lv, Jing Gao, Jingwen Yang, Ying Zou, Jun Chen, Yujing Sun, Jia Song, Yiran Liu, Liming Wang, Longqing Xia, Shijia Yu, Zichun Wei, Li Chen & Xinguo Hou

  2. Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, Shandong, China

    Li Chen & Xinguo Hou

  3. Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, Shandong, China

    Li Chen & Xinguo Hou

  4. Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 250012, Shandong, China

    Li Chen & Xinguo Hou

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  1. Xiaoyu Lv
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Contributions

X.L. designed and carried out experiments. J.G., J.Y., Y.Z., and Y.L. assisted with the paper draft. J.C. and Y.S. monitored the progress of experiments and revised the paper. J.S., L.W., and L.X. helped in designing the study. S.Y. and Z.W. helped analyze clinical data. L.C. and X.H. conceived and designed the study.

Corresponding author

Correspondence to Xinguo Hou.

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The authors declare no competing interests.

Ethical approval

All procedures performed in the study involving human participants were performed under the ethical standards of the institutional and/or national research councils and the Declaration of Helsinki. The study was approved by the Ethics Committee of Qilu Hospital of Shandong University (No.: KYLL-202308-033).

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All subjects included in this study voluntarily signed an informed consent form, which was reviewed by the Ethics Committee of Qilu Hospital of Shandong University. The authors affirm that human research participants provided informed consent for publication of the images in Fig. 1.

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Lv, X., Gao, J., Yang, J. et al. Clinical and functional characterization of a novel KCNJ11 (c.101G > A, p.R34H) mutation associated with maturity-onset diabetes mellitus of the young type 13. Endocrine (2024). https://doi.org/10.1007/s12020-024-03873-6

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