Abstract：
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.
摘要：
储存操作的钙进入（SOCE）在维持细胞钙稳态中起着至关重要的作用。这种机制涉及蛋白质，如基质相互作用分子1(STIM1)和ORAI1。编码这些蛋白质的基因突变，特别是STIM1，可以导致各种疾病，包括与严重联合免疫缺陷相关的CRAC信道病。在这里，我们描述了一个新的纯合突变，NM_003156c.792-3C>G，在患有CRAC信道病临床特征的患者的STIM1中，包括免疫系统缺陷和肌肉无力.功能分析揭示了患者细胞中三种不同的剪接形式：野生型，外显子7跳绳,和内含子保留。钙内流分析显示患者细胞中SOCE受损，表明STIM1功能丧失。我们开发了一种改善STIM1剪接的反义寡核苷酸治疗，并强调了其作为治疗方法的潜力。我们的发现提供了对STIM1突变的复杂影响的见解，并阐明了患者多方面的临床表现。
