叶酸
生物
外周血单个核细胞
甲氨蝶呤
溶质载体族
细胞毒性
免疫学
癌症研究
分子生物学
生物化学
运输机
体外
遗传学
基因
化疗
氟尿嘧啶
作者
Veysel Gök,Şerife Erdem,Yeşim Haliloğlu,Atıl Bişgin,Serkan Belkaya,Kemal Erdem Başaran,Mehmed Fatih Canatan,Alper Özcan,Ebru Yılmaz,Can Acıpayam,Musa Karakükçü,Halit Canatan,Hüseyin Per,Türkan Patıroğlu,Ahmet Eken,Ekrem Ünal
标识
DOI:10.1038/s41435-022-00191-7
摘要
Insufficient dietary folate intake, hereditary malabsorption, or defects in folate transport may lead to combined immunodeficiency (CID). Although loss of function mutations in the major intestinal folate transporter PCFT/SLC46A1 was shown to be associated with CID, the evidence for pathogenic variants of RFC/SLC19A1 resulting in immunodeficiency was lacking. We report two cousins carrying a homozygous pathogenic variant c.1042 G > A, resulting in p.G348R substitution who showed symptoms of immunodeficiency associated with defects of folate transport. SLC19A1 expression by peripheral blood mononuclear cells (PBMC) was quantified by real-time qPCR and immunostaining. T cell proliferation, methotrexate resistance, NK cell cytotoxicity, Treg cells and cytokine production by T cells were examined by flow cytometric assays. Patients were treated with and benefited from folinic acid. Studies revealed normal NK cell cytotoxicity, Treg cell counts, and naive-memory T cell percentages. Although SLC19A1 mRNA and protein expression were unaltered, remarkably, mitogen induced-T cell proliferation was significantly reduced at suboptimal folic acid and supraoptimal folinic acid concentrations. In addition, patients' PBMCs were resistant to methotrexate-induced apoptosis supporting a functionally defective SLC19A1. This study presents the second pathogenic SLC19A1 variant in the literature, providing the first experimental evidence that functionally defective variants of SLC19A1 may present with symptoms of immunodeficiency.
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