Immunodeficiency associated with a novel functionally defective variant of SLC19A1 benefits from folinic acid treatment

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buir.contributor.authorBelkaya, Serkan
buir.contributor.orcidBelkaya, Serkan|0000-0003-4214-382X
dc.contributor.authorGök, V.
dc.contributor.authorErdem, Ş.
dc.contributor.authorHaliloğlu, Y.
dc.contributor.authorBişgin, A.
dc.contributor.authorBelkaya, Serkan
dc.contributor.authorBaşaran, K. E.
dc.contributor.authorCanatan, M. F.
dc.contributor.authorÖzcan, A.
dc.contributor.authorYılmaz, E.
dc.contributor.authorAcıpayam, C.
dc.contributor.authorKarakükcü, M.
dc.contributor.authorCanatan, H.
dc.contributor.authorPer, H.
dc.contributor.authorPatıroğlu, T.
dc.contributor.authorEken, A.
dc.contributor.authorÜnal, E.
dc.date.accessioned2023-02-15T13:20:02Z
dc.date.available2023-02-15T13:20:02Z
dc.date.issued2022-12-15
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractInsufficient 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.en_US
dc.identifier.doi10.1038/s41435-022-00191-7en_US
dc.identifier.eissn1476-5470
dc.identifier.issn1466-4879
dc.identifier.urihttp://hdl.handle.net/11693/111371
dc.language.isoEnglishen_US
dc.publisherSpringer Natureen_US
dc.relation.isversionofhttps://dx.doi.org/10.1038/s41435-022-00191-7en_US
dc.source.titleGenes and Immunityen_US
dc.titleImmunodeficiency associated with a novel functionally defective variant of SLC19A1 benefits from folinic acid treatmenten_US
dc.typeArticleen_US

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