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

Veysel Gök, Şerife Erdem, Yeşim Haliloğlu, Atıl Bişgin, Serkan Belkaya, Kemal Erdem Başaran, Mehmed Fatih Canatan, Alper Özcan, Ebru Yılmaz, Can Acıpayam, Musa Karakükcü, Halit Canatan, Hüseyin Per, Türkan Patıroğlu, Ahmet Eken, Ekrem Ünal

Journal: Genes and immunity 2023;24(1):12-20

PMID: 36517554

Full Text on Nature Publishing Group View on PubMed

Abstract

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.

Address: Department of Pediatrics, Division of Pediatric Hematology & Oncology, Faculty of Medicine, Erciyes University, Kayseri, Türkiye.; Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri, Türkiye.; Department of Medical Biology, Faculty of Medicine, Erciyes University, Kayseri, Türkiye.; Department of Medical Genetics, Faculty of Medicine, Çukurova University, Adana, Türkiye.; Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Türkiye.; Department of Physiology, Faculty of Medicine, Erciyes University, Kayseri, Türkiye.; Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri, Türkiye.; Department of Pediatrics, Division of Pediatric Hematology & Oncology, Faculty of Medicine, Sütçü İmam University, Kahramanmaraş, Türkiye.; Department of Medical Biology, Faculty of Medicine, Erciyes University, Kayseri, Türkiye.; Department of Pediatrics, Division of Pediatric Neurology, Faculty of Medicine, Erciyes University, Kayseri, Türkiye.; Department of Pediatrics, Division of Pediatric Hematology & Oncology, Faculty of Medicine, Erciyes University, Kayseri, Türkiye.; Department of Pediatrics, Division of Pediatric Immunology, Faculty of Medicine, Erciyes University, Kayseri, Türkiye.; Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri, Türkiye. [email protected].; Department of Medical Biology, Faculty of Medicine, Erciyes University, Kayseri, Türkiye. [email protected].; Department of Pediatrics, Division of Pediatric Hematology & Oncology, Faculty of Medicine, Erciyes University, Kayseri, Türkiye. [email protected].; Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri, Türkiye. [email protected].; Department of Blood Banking and Transfusion Medicine, Health Science Institution, Erciyes University, Kayseri, Türkiye. [email protected].

DOI: 10.1038/s41435-022-00191-7

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MeSH Terms: Humans, Folic Acid, Leucovorin, Leukocytes, Mononuclear, Methotrexate, Proton-Coupled Folate Transporter, Reduced Folate Carrier Protein, Immunologic Deficiency Syndromes