title: Increased THEMIS First Exon Usage in CD4+ T-Cells Is Associated with a Genotype that Is Protective against Multiple Sclerosis.
abstract: Multiple sclerosis is an autoimmune disease of the central nervous system. Genome wide association studies have identified over 100 common variants associated with multiple sclerosis, the majority of which implicate immunologically relevant genes, particularly those involved in T-cell development. SNP rs13204742 at the THEMIS/PTPRK locus is one such variant. Here, we have demonstrated mutually exclusive use of exon 1 and 2 amongst 16 novel THEMIS isoforms. We also show inverse correlation between THEMIS expression in human CD4+ T-cells and dosage of the multiple sclerosis risk allele at rs13204742, driven by reduced expression of exon 1- containing isoforms. In silico analysis suggests that this may be due to cell-specific, allele-dependent binding of the transcription factors FoxP3 and/or E47. Research exploring the functional implications of GWAS variants is important for gaining an understanding of disease pathogenesis, with the ultimate aim of identifying new therapeutic targets.
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Jessica L
authors.identifier: http://orcid.org/0000-0002-8888-1441
authors.initials: JL
authors.lastname: Davies
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Sara
authors.initials: S
authors.lastname: Thompson
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Harpreet
authors.initials: H
authors.lastname: Kaur-Sandhu
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Sawcer
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Alasdair
authors.initials: A
authors.lastname: Coles
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Ban
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Joanne
authors.initials: J
authors.lastname: Jones
mesh_terms: D000328:Adult; D000483:Alleles; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D020033:Protein Isoforms; C557796:thymocyte-expressed molecule involved in selection, human