Benedicte Alary , Pascal Cintas , Corentin Claude , Olivier Dellis , Corinne Thèze , Charles Van Goethem , Mireille Cossée , Martin Krahn , Valérie Delague , Marc Bartoli
{"title":"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","authors":"Benedicte Alary , Pascal Cintas , Corentin Claude , Olivier Dellis , Corinne Thèze , Charles Van Goethem , Mireille Cossée , Martin Krahn , Valérie Delague , Marc Bartoli","doi":"10.1016/j.clim.2024.110306","DOIUrl":null,"url":null,"abstract":"<div><p>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 <em>STIM1</em> 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 <em>STIM1</em> splicing and highlighted its potential as a therapeutic approach. Our findings provide insights into the complex effects of <em>STIM1</em> mutations and shed light on the multifaceted clinical presentation of the patient.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5000,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1521661624004157/pdfft?md5=598d2d3cc8fdad3fd207d9ab0d1e7045&pid=1-s2.0-S1521661624004157-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Store-operated calcium entry dysfunction in CRAC channelopathy: Insights from a novel STIM1 mutation\",\"authors\":\"Benedicte Alary , Pascal Cintas , Corentin Claude , Olivier Dellis , Corinne Thèze , Charles Van Goethem , Mireille Cossée , Martin Krahn , Valérie Delague , Marc Bartoli\",\"doi\":\"10.1016/j.clim.2024.110306\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>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 <em>STIM1</em> 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 <em>STIM1</em> splicing and highlighted its potential as a therapeutic approach. Our findings provide insights into the complex effects of <em>STIM1</em> mutations and shed light on the multifaceted clinical presentation of the patient.</p></div>\",\"PeriodicalId\":10392,\"journal\":{\"name\":\"Clinical immunology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.5000,\"publicationDate\":\"2024-07-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S1521661624004157/pdfft?md5=598d2d3cc8fdad3fd207d9ab0d1e7045&pid=1-s2.0-S1521661624004157-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1521661624004157\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical immunology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1521661624004157","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
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.
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.