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- W4286008478 abstract "Abstract Insufficient dietary folate intake, hereditary malabsorption, or defects in folate metabolism 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. In this study, we report two cousins carrying a homozygous pathogenic variant c.1042G>A, resulting in p.G348R substitution who showed clinical symptoms of immunodeficiency associated with defects of folate metabolism. The mutation was identified by whole-exome sequencing. 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. Both patients were treated with and clinically benefited from folinic acid (FA). Functional 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 sub- and supraoptimal folic acid concentrations. In addition, both patients’ PBMCs were resistant to methotrexate-induced apoptosis supporting a functionally defective SLC19A1 variant. This study, to our knowledge, presents the second pathogenic SLC19A1 variant in the literature, providing the first experimental evidence that loss of function mutations in SLC19A1 may present with symptoms of immunodeficiency, and that those defects could benefit from FA supplementation." @default.
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- W4286008478 date "2022-07-20" @default.
- W4286008478 modified "2023-10-15" @default.
- W4286008478 title "A Novel Loss of Function Variant of SLC19A1 Presented with Immunodeficiency and Benefited from Folinic Acid Treatment" @default.
- W4286008478 doi "https://doi.org/10.21203/rs.3.rs-1866280/v1" @default.
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