Candidate Genes
Development of autoimmune diseases is the result of a complex interplay between hereditary and environmental factors, with multiple genes contributing to the pathogenesis in human disease and in experimental models for disease.
The genetic locus Eae39, located on mouse chromosome 5, was previously linked to experimental autoimmune encephalomyelitis (EAE), an experimental model for multiple sclerosis. Subsequently, it was also shown to influence CIA development and severity [8, 10]. Eae39 congenic and sub-congenic lines were bred on the genetic background of the B10.RIII strain [7]. In the present study, the Eae39 sub-locus, Eae39r, was investigated. This locus comprises four protein-coding genes: Mediator complex subunit 13-like (Med13l), T-box transcription factor 3 (Tbx3), T-box transcription factor 5 (Tbx5), and Probable RNA-binding protein 19 (Rbm19). The authors previously showed that genetic polymorphisms in Med13L do not affect the immune phenotype in BR.RIIIS/J-Eae39r congenic mice and are predicted to be non-disease associated (Sardar et al., 2018).BR.RIIIS/J-Eae39r congenic mice were produced by introduction of the Eae39r fragment from the CIA-resistant RIIIS/J donor strain, purchased from Jackson Laboratory (Bar Harbor, ME, USA), to the CIA susceptible B10.RIII background strain, provided by J. Klein (Tbingen, Germany), as previously described [8]. The sub-congenic line BR.RIIIS/J-Eae39r2 was produced by further inter-crossing heterozygous BR.RIIIS/J-Eae39r mice. Purified genomic DNA was used for genotyping by high-resolution melting (HRM) SNP genotyping for rs33583463 (5:118596773 bp; mouse genome assembly GRCm38) and rs29824716 (5:120043597 bp; mouse genome assembly GRCm38).Gene expression studies have revealed differential expression of Tbx3 in B cells, where low expression was accompanied by a higher B cell response upon B cell receptor stimulation in vitro. Furthermore, we showed that serum TBX3 levels rise concomitantly with increasing severity of CIA. From these results, the authors suggest that TBX3 is a novel factor important for the regulation of gene transcription in the immune system and that genetic polymorphisms, resulting in lower expression of Tbx3, are contributing to a more severe form of CIA and high titers of autoantibodies. They also propose TBX3 as a putative diagnostic biomarker for rheumatoid arthritis.
Mapping and Phenotype information for this QTL,
its variants and associated markers
Various Eae39 congenic strains of mice were developed by breeding RIIIS/J (donor) onto the B10.RIII background (recipient). The Eae39 interval in previous backcross experiments is between D5Mit259 and D5Mit136. In constructing these congenics the authors goal was to further dissect the E39 locus as to its effect on collagen induced arthritis (CIA). A marker near D5Mit113(78 Mbp) promoted disease resistance whereas RIIIS/J alleles at D5Mit136 and D5Mit367 protected against CIA. MGI named these two regions as Eae39s and Eae39r respectively
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