Investigation of novel variations of ORAI1 gene and their association with Kawasaki disease

Thiha, Kyaw; Mashimo, Yoichi; Suzuki, Hiroyuki; Hamada, Hiromichi; Hata, Akira; Hara, Toshiro; Tanaka, Toshihiro; Ito, Kei; Onouchi, Yoshihiro

doi:10.1038/s10038-019-0588-2

Cited by 9 publications

(12 citation statements)

References 37 publications

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“…In addition to STIM1, genetic variants in another key component of store-operated calcium channel, Orai1, are critical for complex diseases, especially for inflammatory diseases. Based on the genetic association study, For example, Orai1 polymorphisms have been shown to associate with the susceptibility for recurrence of calcium nephrolithiasis, Kawasaki disease and atopic dermatitis [36,37,40]. Here, our study revealed different findings.…”

Section: Discussionmentioning

confidence: 59%

Germline Genetic Association between Stromal Interaction Molecule 1 (STIM1) and Clinical Outcomes in Breast Cancer Patients

Huang

Lin

Yang

et al. 2020

JPM

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Among all cancers in women, breast cancer has the highest incidence. The mortality of breast cancer is highly associated with metastasis. Migration and malignant transformation of cancer cells have been reported to be modulated by store-operated calcium (SOC) channels, which control calcium signaling and cell proliferation pathways. Stromal interaction molecule 1 (STIM1) is a calcium sensor in the endoplasmic reticulum, triggering the activation of store-operated calcium signaling. However, the clinical relevance of STIM1 in breast cancer is still unclear. Here, we recruited 348 breast cancer patients and conducted a genetic association study to address this question. Four tagging germline single nucleotide variants (SNVs) in STIM1 were selected and RNA sequencing data of 525 breast cancer samples from The Cancer Genome Atlas (TCGA) database were evaluated. The results show that rs2304891 and rs3750996 were correlated with clinical stage of breast cancer. Expression quantitative trait loci (eQTL) analysis indicated that risk G allele of STIM1 contributed to the higher expression of STIM1. In addition, we found an increased risk of rs2304891 G allele and rs3750996 A allele in estrogen receptor (ER) positive and progesterone receptor (PR) positive patients. In conclusion, our results suggest that germline SNV, rs2304891 and rs3750996 as well as STIM1 expression are important biomarkers for the prediction of clinical outcomes in breast cancer patients.

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Section: Discussionmentioning

confidence: 59%

Germline Genetic Association between Stromal Interaction Molecule 1 (STIM1) and Clinical Outcomes in Breast Cancer Patients

Huang

Lin

Yang

et al. 2020

JPM

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“…SNVs in ITPKC and CASP3 are reported to be associated with resistance to IVIG [ 17 ]. Furthermore, recent observations have revealed that one SNV in ORAI1 in a refractory patient caused a gain of function, leading to constitutive Ca 2+ entry into immune cells, which upregulated the calcineurin/NFAT signaling pathway [ 18 ]. Therefore, the SNV in ORAI1 (rs3741596) detected in the present case might be associated with its refractory nature.…”

Section: Discussionmentioning

confidence: 99%

Combined Single Nucleotide Variants of ORAI1 and BLK in a Child with Refractory Kawasaki Disease

et al. 2021

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Kawasaki disease (KD) is a systemic vasculitis with an unknown etiology affecting young children. Although intravenous immunoglobulin (IVIG) plus acetylsalicylic acid is effective in most cases, approximately 10–20% of patients do not respond to this therapy. An 8-month-old boy was admitted to a local hospital with the presumptive diagnosis of KD. He received IVIG twice and four series of methylprednisolone pulse therapy from the third to the tenth day of illness. Despite these treatments, his fever persisted with the development of moderate dilatations of the coronary arteries. A diagnosis of refractory KD was made, and infliximab with oral prednisolone was administered without success. Defervescence was finally achieved by cyclosporine A, an inhibitor of the signaling pathway of the calcineurin/nuclear factor of activated T cells (NFAT). Whole-genome sequencing of his deoxyribonucleic acid samples disclosed two single nucleotide variants (SNVs) in disease-susceptibility genes in Japanese KD patients, ORAI1 (rs3741596) and BLK (rs2254546). In summary, the refractory nature of the present case could be explained by the presence of combined SNVs in susceptibility genes associated with upregulation of the calcineurin/NFAT signaling pathway. It may provide insights for stratifying KD patients based on the SNVs in their susceptibility genes.

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“…The implication of ORAI1 in human cardiovascular abnormalities was highlighted by the reported association of ORAI1 mutations with Kawasaki disease (KD) susceptibility, which is the leading cause of cardiovascular complications during childhood. These studies have identified rare missense variants in KD patients (Onouchi et al, 2016;Thiha et al, 2019). The reported variants in KD patients, interestingly, include a variant that cause p.Gly98Asp mutation within the TM1 domain that generates the ion conduction pore, which is a mutation known to lead to a constitutive ORAI1 channel activation (Zhang et al, 2011a).…”

Section: Evidence Implicating Orai1 In Pathological Vascular Remodelling In Atherosclerosis and Nihmentioning

confidence: 99%

ORAI1 Ca2+ Channel as a Therapeutic Target in Pathological Vascular Remodelling

Shawer

Norman

Cheng

et al. 2021

Front. Cell Dev. Biol.

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In the adult, vascular smooth muscle cells (VSMC) are normally physiologically quiescent, arranged circumferentially in one or more layers within blood vessel walls. Remodelling of native VSMC to a proliferative state for vascular development, adaptation or repair is driven by platelet-derived growth factor (PDGF). A key effector downstream of PDGF receptors is store-operated calcium entry (SOCE) mediated through the plasma membrane calcium ion channel, ORAI1, which is activated by the endoplasmic reticulum (ER) calcium store sensor, stromal interaction molecule-1 (STIM1). This SOCE was shown to play fundamental roles in the pathological remodelling of VSMC. Exciting transgenic lineage-tracing studies have revealed that the contribution of the phenotypically-modulated VSMC in atherosclerotic plaque formation is more significant than previously appreciated, and growing evidence supports the relevance of ORAI1 signalling in this pathologic remodelling. ORAI1 has also emerged as an attractive potential therapeutic target as it is accessible to extracellular compound inhibition. This is further supported by the progression of several ORAI1 inhibitors into clinical trials. Here we discuss the current knowledge of ORAI1-mediated signalling in pathologic vascular remodelling, particularly in the settings of atherosclerotic cardiovascular diseases (CVDs) and neointimal hyperplasia, and the recent developments in our understanding of the mechanisms by which ORAI1 coordinates VSMC phenotypic remodelling, through the activation of key transcription factor, nuclear factor of activated T-cell (NFAT). In addition, we discuss advances in therapeutic strategies aimed at the ORAI1 target.

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Investigation of novel variations of ORAI1 gene and their association with Kawasaki disease

Cited by 9 publications

References 37 publications

Germline Genetic Association between Stromal Interaction Molecule 1 (STIM1) and Clinical Outcomes in Breast Cancer Patients

Germline Genetic Association between Stromal Interaction Molecule 1 (STIM1) and Clinical Outcomes in Breast Cancer Patients

Combined Single Nucleotide Variants of ORAI1 and BLK in a Child with Refractory Kawasaki Disease

ORAI1 Ca2+ Channel as a Therapeutic Target in Pathological Vascular Remodelling

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