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.
Highlights
Multiple sclerosis (MS) is the most common cause of chronic neurological disability in young adults
It is known that genomic exon 5 of thymocyte expressed molecule involved in selection (THEMIS) encodes one of its two CABIT domains, a proline rich region (PRR) required for protein-protein interactions, and a YY-motif required for interaction with Grb2, making it crucial to the function of THEMIS[26]
110 common variants have been shown to be associated with susceptibility to multiple sclerosis[3], and much current research is aimed at understanding the functional effects of these variants
Summary
Multiple sclerosis (MS) is the most common cause of chronic neurological disability in young adults. Genome wide association studies (GWAS)[2] and subsequent fine mapping of risk loci (Immunochip)[3] have identified 110 common MS risk variants, the majority of which lie within 50kb of genes with immunological function, genes involved in T-cell development[2]. One of the implicated genomic regions lies on chromosome 6q and contains two genes critically important for T-cell development: thymocyte expressed molecule involved in selection (THEMIS) and protein tyrosine phosphatase, receptor type, κ (PTPRK). Association with this locus was first identified in the 2011 GWAS, in which the most associated SNP was rs802734, an intergenic SNP located 56 kb 5’ of THEMIS and 11 kb 3’ of PTPRK [2]. Subsequent finemapping of this region in the Immunochip study identified rs13204742 as the lead SNP, a PLOS ONE | DOI:10.1371/journal.pone.0158327 July 20, 2016
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
