Case Report: Functional characterization of a missense variant in INSR associated with hypoketotic hypoglycemia.

IF 2.1 3区 医学 Q2 PEDIATRICS
Frontiers in Pediatrics Pub Date : 2024-10-17 eCollection Date: 2024-01-01 DOI:10.3389/fped.2024.1493280
Herodes Guzman, Lauren M Mitteer, Pan Chen, Christine A Juliana, Kara Boodhansingh, Katherine Lord, Arupa Ganguly, Diva D De Leon
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引用次数: 0

Abstract

Hypoketotic hypoglycemia due to dysregulated insulin secretion is the most common cause of persistent hypoglycemia in children. However, this type of hypoglycemia can also result from defects in the insulin signaling pathway. Distinguishing between the two is important for informing treatment decisions. Here we describe the case of a 10-year-old female with fasting and postprandial hypoglycemia who was found to have a missense variant in the INSR gene, which we functionally characterized. The proband presented with fasting and postprandial hypoglycemia at age six. Diagnostic evaluation was consistent with hypoketotic hypoglycemia suspected to be due to hyperinsulinism, and she was treated with diazoxide. Whole exome sequencing identified a maternally inherited heterozygous missense variant in INSR. Phenotypic studies on the mother were consistent with postprandial hypoglycemia. Phosphorylated Akt and ERK1/2 levels were higher at baseline and in response to stimulation with insulin in 3T3-L1 cells expressing mutant INSR compared to cells expressing wild type INSR. Thus, herein we present a heterozygous missense variant in INSR (c.1151A>G, p.Asn384Ser) that results in constitutive and increased activation of the human insulin receptor, leading to both fasting and postprandial hypoglycemia.

病例报告:与低血糖有关的 INSR 错义变体的功能特征。
胰岛素分泌失调导致的低酮低血糖是儿童持续性低血糖最常见的原因。然而,胰岛素信号通路缺陷也可能导致这种类型的低血糖。区分这两种情况对于做出治疗决定非常重要。在这里,我们描述了一个患有空腹和餐后低血糖症的 10 岁女性病例,她被发现患有 INSR 基因的错义变异,我们对该基因进行了功能鉴定。该患者六岁时出现空腹和餐后低血糖症。诊断评估结果与低酮低血糖症一致,怀疑是高胰岛素血症引起的,她接受了双唑醇治疗。全外显子组测序确定了INSR的母系遗传性杂合错义变异。对母亲的表型研究与餐后低血糖症一致。与表达野生型 INSR 的细胞相比,在表达突变 INSR 的 3T3-L1 细胞中,磷酸化 Akt 和 ERK1/2 水平在基线和胰岛素刺激下均较高。因此,我们在本文中提出了一种 INSR 杂合子错义变体(c.1151A>G, p.Asn384Ser),这种变体会导致人类胰岛素受体的构成性活化和活化增强,从而导致空腹和餐后低血糖。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Frontiers in Pediatrics
Frontiers in Pediatrics Medicine-Pediatrics, Perinatology and Child Health
CiteScore
3.60
自引率
7.70%
发文量
2132
审稿时长
14 weeks
期刊介绍: Frontiers in Pediatrics (Impact Factor 2.33) publishes rigorously peer-reviewed research broadly across the field, from basic to clinical research that meets ongoing challenges in pediatric patient care and child health. Field Chief Editors Arjan Te Pas at Leiden University and Michael L. Moritz at the Children''s Hospital of Pittsburgh are supported by an outstanding Editorial Board of international experts. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide. Frontiers in Pediatrics also features Research Topics, Frontiers special theme-focused issues managed by Guest Associate Editors, addressing important areas in pediatrics. In this fashion, Frontiers serves as an outlet to publish the broadest aspects of pediatrics in both basic and clinical research, including high-quality reviews, case reports, editorials and commentaries related to all aspects of pediatrics.
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