Very early onset inflammatory bowel disease with compound heterozygous variants in Nuclear Factor of Activated T cell 5

A female with very early onset inflammatory bowel disease (VEO-IBD) was shown to carry two compound heterozygous missense variants in Nuclear Factor of Activated T cells 5 and have impaired induction iTregs. The NFAT5 may be the cause lack iTregs consequently development VEO-IBD. Primary immunodeficiencies (PID) are inborn errors immunity causing an increased susceptibility infections, or dysregulated autoimmunity autoinflammation [1]. Inflammatory (IBD) can considered a immune response environmental triggers genetically susceptible hosts. It is assumed that between 20 30% patients suffering from IBD underlying monogenetic etiology [2]. We describe patient VEO-IBD who carries transcription factor (NFAT5). has no family history PID IBD. At age 4.5 years she diagnosed Crohn's disease. 11, diagnosis sarcoidosis affecting cervical lymph nodes lungs made. During following years, developed severe lung fibrosis, probable side effect treatment sulfasalazine. 23, colectomy creation ileostomy performed due control her 26, screened for but had normal levels immunoglobulins chronic granulomatous excluded. 30 age, aspergilloma right currently treated Posaconazole (for complete medical history, see Supporting Information). 35, referred second evaluation PID. She received prednisolone 10 mg per day. Immunological assessment revealed low plasma IgG (4.9 g/L) IgM (0.19 g/L), whereas IgA (1.29 IgE were (<115 × 103 IU/L). Blood lymphocyte concentration marginally decreased (600–1000/μL) because concentrations B (Fig. 1A). Within B-cell population, fraction transitional naïve low, fractions switched memory cells, blasts, CD21low 1B). T-cell compartment, distributions helper cytotoxic seen 1C). Among T-helper percentage phenotypes phenotypes. only central subset abnormal 1D) (For gating strategy, Information Fig. S1). proliferation assay showed proliferative capacity. Prednisolone influenced results. Whole exome sequencing as previously described [3], except biologically relevant genes listed 2. Of 11 rare detected (Supporting Table S1), NFAT5, c.3752 A>C (Q1251R), c.3902C>G (P1303A) CADD score 25.5 23.6, respectively, (both predicted tolerated by SIFT, Probably Damaging PolyPhen-2) 2A). situated transactivating domains amino acids conserved across species 2D). Sanger healthy father carried c.3752A>C variant mother variant, brother did not any 2B C). In conclusion, potentially deleterious NFAT5. belongs NFAT family, group Rel homology domain proteins. addition comprises NF-κB well four calcineurin-activated proteins, NFAT1-4. activated hyperosmotic stress originally identified key maintaining cellular homeostasis environments [4]. also through receptor Toll-like receptors (TLR), NFAT5-regulated play role responses. activation function complex since different upregulated depending on cell type stimuli [5]. presence inducible Tregs important tolerance gut microbiota. FoxP3 gene harbors several NFAT-binding sites protein interacts NFAT. transcriptional complexes involving activate repress inducing differentiation non-Tregs [6]. controls Tregs, inhibition compromises Treg cells. Knockdown been inhibit both [7]. There increasing evidence Th17/Treg imbalance might crucial monogenic disorders defective IBD-like [1, 8]. Peripheral mononuclear (PBMCs) stimulated anti-CD3, anti-CD28, IL-2, TGF-β induce steroid simulate vivo environment Steroid seem affect induction. our significantly lower compared 2F). mRNA level PBMCs differ controls. expression 2E S2). However, still associated loss experimental model colitis, mice lacking specifically exhibited worsened intestinal pathology higher IFN-γ IL-17A mesenterial [9]. 2015, Boland et al. 19-year-old man haploinsufficiency autoimmune enteropathy [10]. harbored de novo 559 kb deletion at 16q22.1. support importance IBD, they demonstrated reduced biopsies ulcerative colitis disease, study prompted listing error Our report supports association To knowledge, we here first possible linked Tregs. propose iTreg. Lack microbiota causative patient's clinical phenotype prompting further studies diseases. thank Dr. Jose Aramburu, Immunology Lab, Department Experimental Health Sciences, Universitat Pompeu Fabra, Barcelona, providing anti-NFAT5 antibody guidance performing western blot. authors commercial financial conflicts interest peer review this article available https://publons.com/publon/10.1002/eji.202048602 Data openly public repository issues datasets DOIs. Please note: publisher responsible content functionality supporting information supplied authors. Any queries (other than missing content) should directed corresponding author article.