The Minor Variant of the Single-Nucleotide Polymorphism rs3753381 Affects the Activity of a SLAMF1 Enhancer

The SLAMF1 gene encodes CD150, a transmembrane glycoprotein expressed on the surface of T and B-lymphocytes, NK-cells, dendritic cells, and subpopulations of macrophages and basophils. We investigated the functional regulatory polymorphisms of the SLAMF1 locus associated with autoimmune processes, using bioinformatics and a mutational analysis of the regulatory elements overlapping with polymorphic positions. In the reporter gene assay in MP-1 and Raji B-cell lines, the enhancer activity of the regulatory region of the locus containing the rs3753381 polymorphism demonstrated a twofold increase upon the introduction of the rs3753381 minor variant (G → A) associated with myasthenia gravis. An analysis of the nucleotide context in the vicinity of rs3753381 revealed that the minor version of this polymorphism improves several binding sites for the transcription factors of FOX and NFAT, and RXR nuclear receptors. All mutations that disrupt any of these sites lead to a decrease in the enhancer activity both in MP1 and in Raji cells, and each of the two B-cell lines expresses a specific set of these factors. Thus, the minor variant of the rs3753381 polymorphism may contribute to the development of myasthenia gravis by modulating SLAMF1 expression, presumably in pathogenic B-lymphocytes.

[1]  M. Coenen,et al.  Polymorphisms in CD84, IL12B and TNFAIP3 are associated with response to biologics in patients with psoriasis , 2017, The British journal of dermatology.

[2]  L. Motta,et al.  Early‐ and late‐onset psoriasis: a cross‐sectional clinical and immunocytochemical investigation , 2016, The British journal of dermatology.

[3]  K. V. Korneev,et al.  Early B-cell factor 1 (EBF1) is critical for transcriptional control of SLAMF1 gene in human B cells. , 2016, Biochimica et biophysica acta.

[4]  Vladimir B. Bajic,et al.  HOCOMOCO: expansion and enhancement of the collection of transcription factor binding sites models , 2015, Nucleic Acids Res..

[5]  Marion H. Brown,et al.  A polymorphism in a phosphotyrosine signalling motif of CD229 (Ly9, SLAMF3) alters SH2 domain binding and T‐cell activation , 2015, Immunology.

[6]  Caixia Ma,et al.  SLAM–SAP Signaling Promotes Differentiation of IL-17–Producing T Cells and Progression of Experimental Autoimmune Encephalomyelitis , 2014, The Journal of Immunology.

[7]  Brian T. Lee,et al.  The UCSC Genome Browser database: 2015 update , 2014, Nucleic Acids Res..

[8]  A. Marx,et al.  The Association of PTPN22 R620W Polymorphism Is Stronger with Late-Onset AChR-Myasthenia Gravis in Turkey , 2014, PloS one.

[9]  J. Lee,et al.  Whole-Genome Analysis in Korean Patients with Autoimmune Myasthenia Gravis , 2014, Yonsei medical journal.

[10]  Edwin Smith,et al.  Enhancer biology and enhanceropathies , 2014, Nature Structural &Molecular Biology.

[11]  R. Lisak,et al.  Ectopic germinal centers, BAFF and anti-B-cell therapy in myasthenia gravis. , 2013, Autoimmunity reviews.

[12]  A. Kawasaki,et al.  Association of a single nucleotide polymorphism in the SH2D1A intronic region with systemic lupus erythematosus , 2013, Lupus.

[13]  M. Shong,et al.  Upregulated NLRP3 Inflammasome Activation in Patients With Type 2 Diabetes , 2012, Diabetes.

[14]  Soumya Raychaudhuri,et al.  Risk for myasthenia gravis maps to a 151Pro→Ala change in TNIP1 and to human leukocyte antigen‐B*08 , 2012, Annals of neurology.

[15]  Edgar Wingender,et al.  TFClass: an expandable hierarchical classification of human transcription factors , 2012, Nucleic Acids Res..

[16]  Nathan C. Sheffield,et al.  The accessible chromatin landscape of the human genome , 2012, Nature.

[17]  N. Tandon,et al.  Common variants of SLAMF1 and ITLN1 on 1q21 are associated with type 2 diabetes in Indian population , 2012, Journal of Human Genetics.

[18]  Michael N. Alonso,et al.  B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies , 2011, Nature Medicine.

[19]  A. Baxter,et al.  Role of SLAM in NKT Cell Development Revealed by Transgenic Complementation in NOD Mice , 2011, The Journal of Immunology.

[20]  S. Tangye,et al.  SLAM family receptors and SAP adaptors in immunity. , 2011, Annual review of immunology.

[21]  S. Shoelson,et al.  Type 2 diabetes as an inflammatory disease , 2011, Nature Reviews Immunology.

[22]  E. Wakeland,et al.  The role of SLAM/CD2 polymorphisms in systemic autoimmunity. , 2010, Current opinion in immunology.

[23]  R. Young,et al.  Histone H3K27ac separates active from poised enhancers and predicts developmental state , 2010, Proceedings of the National Academy of Sciences.

[24]  Yaofeng Zhao,et al.  Lack of association of the CIITA -168A→G promoter SNP with myasthenia gravis and its role in autoimmunity , 2010, BMC Medical Genetics.

[25]  M. Boes,et al.  SLAM is a microbial sensor that regulates bacterial phagosome functions in macrophages , 2010, Nature Immunology.

[26]  K. Nichols,et al.  Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency. , 2009, The Journal of clinical investigation.

[27]  Y. Kamatani,et al.  Functional SNPs in CD244 increase the risk of rheumatoid arthritis in a Japanese population , 2008, Nature Genetics.

[28]  T. Hudson,et al.  Association of LY9 in UK and Canadian SLE families , 2008, Genes and Immunity.

[29]  C. Mohan,et al.  Regulation of B Cell Tolerance by the Lupus Susceptibility Gene Ly108 , 2006, Science.

[30]  Y. Abe,et al.  Induction of myasthenia by immunization against muscle-specific kinase. , 2006, The Journal of clinical investigation.

[31]  A. Gajra,et al.  Response of myasthenia gravis to rituximab in a patient with non‐Hodgkin lymphoma , 2004, American journal of hematology.

[32]  G. Cheng,et al.  Signaling Lymphocytic Activation Molecule Is Expressed on CD40 Ligand-Activated Dendritic Cells and Directly Augments Production of Inflammatory Cytokines1 , 2001, The Journal of Immunology.

[33]  G. Giaccone,et al.  Circulating Vα24+ Vβ11+ NKT Cell Numbers Are Decreased in a Wide Variety of Diseases That Are Characterized by Autoreactive Tissue Damage , 2001 .

[34]  B. Cocks,et al.  SLAM and its role in T cell activation and Th cell responses , 1997, Immunology and cell biology.

[35]  B. Cocks,et al.  Soluble and Membrane-bound Forms of Signaling Lymphocytic Activation Molecule (SLAM) Induce Proliferation and Ig Synthesis by Activated Human B Lymphocytes , 1997, The Journal of experimental medicine.

[36]  B. Cocks,et al.  A novel receptor involved in T-cell activation , 1995, Nature.

[37]  D. Richman,et al.  Monoclonal anti-acetylcholine receptor antibodies can cause experimental myasthenia , 1980, Nature.

[38]  Richard Bruick.  SUPPLEMENTAL EXPERIMENTAL PROCEDURES , 2012 .

[39]  S. P. Sidorenko,et al.  The dual-function CD150 receptor subfamily: the viral attraction , 2003, Nature Immunology.