engleski

Cell-Line Model of Immunoglobulin G Glycosylation Uncovers Activity of Runx1 as a Potential Modifier of the Immunoglobulin G Glycolisation.

Down syndrome (DS) is a condition caused by trisomy 21 that entails numerous symptoms, one of which are premature signs of aging. As revealed by our recent research, these signs of premature aging are also reflected in plasma-derived immunoglobulin G (IgG) glycosylation, which is a well-known marker of biological age (Krištić et al. 2014). We have recently uncovered that individuals with DS show on average a 19-year increase in biological age when compared to chronologically age-matched controls of normal karyotype, however the mechanism that causes this substantial difference is yet to be discovered. We hypothesize that these differences could be explained by the presence of a third copy of certain chromosome 21 genes, followed by the increased expression of proteins encoded by those genes. One candidate chromosome 21 gene is RUNX1 based on a recent GWAS study which found SNPs around this gene to be associated with human plasma IgG glycosylation (Klarić et al. 2020), and its extra copy has been discovered as an initiator of leukemogenic predisposition in DS (Nižetić and Groet 2012). We here used EBV-immortalized lymphoblastoid cell lines (LCLs) from an individual with DS and their disomic parent and sibling and treated the cells with a chemical inhibitor of the protein encoded by RUNX1. After treatment, the comparison of glycosylation profiles of IgG generated by these LCL cells revealed that inhibition of RUNX1 very significantly affected the glycosylation of IgG from LCLs derived from the disomic controls, yet no significant change in profile was observed in the cell-derived IgG of the person with DS. This finding complies with the aforementioned GWAS results and further implies that RUNX1 could be an important modulator of the general IgG profile in people with a normal number of chromosomes. Other mechanisms may prevail in skewing the glycan profiles in cells from people with DS.

immunoglobulin G glycosylation, Down Syndrome, RUNX1

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