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.

IF 3 3区 医学 Q2 ENDOCRINOLOGY & METABOLISM Endocrine Pub Date : 2024-11-01 Epub Date: 2024-05-18 DOI:10.1007/s12020-024-03873-6
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
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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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一种新型 KCNJ11(c.101G > A, p.R34H)突变的临床和功能特征与成熟期发病的 13 型青年糖尿病有关。
目的:本研究旨在描述一名由KCNJ11(c.101G > A, p.R34H)导致的MODY13患者的临床特征、诊断和治疗过程,以及它如何导致MODY13的发病机制,并探索新的治疗靶点:方法:采用全外显子组测序筛选临床疑似 KCNJ11 基因突变的诊断前个体和家庭成员。采用实时荧光定量 PCR、Western 印迹、钾通道铊通量、葡萄糖刺激胰岛素分泌(GSIS)和免疫荧光检测等方法分析 KCNJ11 突变体对 MIN6 细胞胰岛素分泌的调控。使用动态血糖仪(SIBIONICS)连续监测原发性糖尿病患者14天的每日血糖水平:结果:通过对整个基因外显子的突变筛查,在该患者及其母亲体内发现了 KCNJ11(c.101G > A, p.R34H)杂合子突变。使用野生型和突变型质粒转染 MIN6 后进行的基于细胞的 GSIS 检测显示,该突变损害了胰岛素分泌功能。此外,我们还发现这种分泌功能受损与突变体 KCNJ11 蛋白的功能活性降低以及胰岛素分泌相关外泌蛋白 STXBP1 和 SNAP25 的表达减少有关:我们首次揭示了KCNJ11(c.101G > A, p.R34H)与MODY13相关的致病机制。该突变体可导致 KATP 通道活性改变,降低对葡萄糖刺激的敏感性,并通过下调胰岛素分泌相关的外泌蛋白而损害胰岛β细胞的分泌功能。因此,口服磺脲类药物可通过促胰岛素作用降低血糖水平,对这种突变的患者更有利。
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来源期刊
Endocrine
Endocrine ENDOCRINOLOGY & METABOLISM-
CiteScore
6.50
自引率
5.40%
发文量
295
审稿时长
1.5 months
期刊介绍: Well-established as a major journal in today’s rapidly advancing experimental and clinical research areas, Endocrine publishes original articles devoted to basic (including molecular, cellular and physiological studies), translational and clinical research in all the different fields of endocrinology and metabolism. Articles will be accepted based on peer-reviews, priority, and editorial decision. Invited reviews, mini-reviews and viewpoints on relevant pathophysiological and clinical topics, as well as Editorials on articles appearing in the Journal, are published. Unsolicited Editorials will be evaluated by the editorial team. Outcomes of scientific meetings, as well as guidelines and position statements, may be submitted. The Journal also considers special feature articles in the field of endocrine genetics and epigenetics, as well as articles devoted to novel methods and techniques in endocrinology. Endocrine covers controversial, clinical endocrine issues. Meta-analyses on endocrine and metabolic topics are also accepted. Descriptions of single clinical cases and/or small patients studies are not published unless of exceptional interest. However, reports of novel imaging studies and endocrine side effects in single patients may be considered. Research letters and letters to the editor related or unrelated to recently published articles can be submitted. Endocrine covers leading topics in endocrinology such as neuroendocrinology, pituitary and hypothalamic peptides, thyroid physiological and clinical aspects, bone and mineral metabolism and osteoporosis, obesity, lipid and energy metabolism and food intake control, insulin, Type 1 and Type 2 diabetes, hormones of male and female reproduction, adrenal diseases pediatric and geriatric endocrinology, endocrine hypertension and endocrine oncology.
期刊最新文献
Correction to: Therapeutic patient education and treatment intensification of diabetes and hypertension in subjects with newly diagnosed type 2 diabetes mellitus: a longitudinal study. Correction: Timing of the repeat thyroid fine-needle aspiration biopsy: does early repeat biopsy change the rate of nondiagnostic or atypia of undetermined significance cytology result? Hematological toxicities with Lutathera® for neuroendocrine neoplasms: post-marketing surveillance data from the US-FDA. SGLT2 inhibitors may reduce non-small cell lung cancer and not increase various neoplasms including several skin cancers. Clarification on the role of thyroid scintigraphy in the era of TIRADS: a response to Trimboli et al. (2024).
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