Investigating the expression of Y76C and D51A gene variants in indivduals with hypothyroidism and diabetes

Double negative (DN) thymocytes differentiate into mature TCRαβ- or TCRgδ-expressing T cells. Early thymopoiesis is associated with simultaneous TCR-β, TCR-δ and TCR-g rearrangement at the TCRB, TCRA-TCRD and TCRG locus, respectively. Following productive TCRB locus rearrangement, the TCR-β chain will dimerize with the pre-TCRα protein. The resulting pre-TCR is expressed at the cell surface and will promote a burst of proliferation and differentiation to CD4 and CD8 double positive (DP) thymocytes. At the DP stage, the TCRA locus starts to rearrange. A productive TCRa rearrangement leads to TCR-6 deletion within the TCRA-TCRD locus, and a TCRaP will be expressed at cell surface. This TCRα will go through positive selection in the thymic cortex to ensure recognition of an MHC-I or -II, and differentiation to CD4 or CD8 single positive (SP) thymocytes. To avoid the production of autoreactive T cells, SP thymocytes go through negative selection against self-antigens in the thymic medulla. Autoreactive thymocytes either die by apoptosis (clonal deletion) or differentiate into regulatory T cells (clonal diversion). In this context, the phenotype of human pre-TCRα deficiency is unknown. The two natural variants (D51A and Y76C) were found to be severely hypomorphic for the ability of PTCRA to stabilize CD3 and TCR-β at the cell surface of a TCR-α deficient Jurkat cell line. In addition, loss of function mutations was identified in our patients, and these two mutations also showed loss of function for their ability to induce the activation marker CD69 in the TCR-α deficient Jurkat cell system. The PTCRA gene variants are common in the Gulf, and its homozygosity underlies hypothyroidism, which is very high in Kuwait. The PTCRA SNP rs200942121 is present in about 2% of the population and is higher (near 4%) in individuals with type 2 diabetics (T2D). Our data also showed that the ethnicity of the studied individuals with T2D were Kuwaiti of Persian origin, which was similar to other population studies. We hypothesize that PTCRA gene variants are enriched, and that the D51A variant is a common allele of autoimmunity, in the Kuwaiti population. Therefore, we aim to identify and characterize individuals with the Y76C or D51A variants in the Kuwaiti population.