CRAC 通道病中的储能钙离子进入功能障碍:新型 STIM1 基因突变的启示

IF 4.5 3区 医学 Q2 IMMUNOLOGY
Benedicte Alary , Pascal Cintas , Corentin Claude , Olivier Dellis , Corinne Thèze , Charles Van Goethem , Mireille Cossée , Martin Krahn , Valérie Delague , Marc Bartoli
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引用次数: 0

摘要

储能钙离子通道(SOCE)在维持细胞钙平衡方面发挥着至关重要的作用。这一机制涉及基质相互作用分子 1(STIM1)和 ORAI1 等蛋白。编码这些蛋白(尤其是 STIM1)的基因突变可导致多种疾病,包括与重症联合免疫缺陷相关的 CRAC 通道病。在本文中,我们描述了 STIM1 中的一个新型同源突变 NM_003156 c.792-3C > G,该突变的患者具有 CRAC 通道病的临床特征,包括免疫系统缺陷和肌无力。功能分析显示,患者细胞中有三种不同的剪接形式:野生型、外显子 7 跳接和内含子保留。钙离子流入分析显示,患者细胞中的 SOCE 功能受损,表明 STIM1 功能丧失。我们开发了一种反义寡核苷酸治疗方法,可改善 STIM1 的剪接,并强调了其作为一种治疗方法的潜力。我们的研究结果让人们深入了解了 STIM1 突变的复杂影响,并揭示了患者多方面的临床表现。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Store-operated calcium entry dysfunction in CRAC channelopathy: Insights from a novel STIM1 mutation

Store-operated calcium entry (SOCE) plays a crucial role in maintaining cellular calcium homeostasis. This mechanism involves proteins, such as stromal interaction molecule 1 (STIM1) and ORAI1. Mutations in the genes encoding these proteins, especially STIM1, can lead to various diseases, including CRAC channelopathies associated with severe combined immunodeficiency. Herein, we describe a novel homozygous mutation, NM_003156 c.792-3C > G, in STIM1 in a patient with a clinical profile of CRAC channelopathy, including immune system deficiencies and muscle weakness. Functional analyses revealed three distinct spliced forms in the patient cells: wild-type, exon 7 skipping, and intronic retention. Calcium influx analysis revealed impaired SOCE in the patient cells, indicating a loss of STIM1 function. We developed an antisense oligonucleotide treatment that improves STIM1 splicing and highlighted its potential as a therapeutic approach. Our findings provide insights into the complex effects of STIM1 mutations and shed light on the multifaceted clinical presentation of the patient.

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来源期刊
Clinical immunology
Clinical immunology 医学-免疫学
CiteScore
12.30
自引率
1.20%
发文量
212
审稿时长
34 days
期刊介绍: Clinical Immunology publishes original research delving into the molecular and cellular foundations of immunological diseases. Additionally, the journal includes reviews covering timely subjects in basic immunology, along with case reports and letters to the editor.
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