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Background: Specific cell types from people with Down syndrome (DS) show faster accumulation of DNA damage and epigenetic senescence marks. Causative mechanisms remain un-proven ranging from amplified chromosomal instability to actions of chromosome 21 genes. Plasma immunoglobulin G (IgG) glycosylation profiles are established as a reliable predictor of biological and chronological ageing. Methods: We performed IgG glycan profiling of n=246 individuals with DS (208 adults and 38 children) clinically characterised for co- morbidities, from three European countries, and compared these to age-, sex- and demography- matched general populations. Results: We uncovered very significantly increased IgG glycosylation ageing marks associated with DS, beginning in early childhood. Average levels of IgG glycans without galactose (G0) and those with two galactoses (G2) as a function of age in persons with DS corresponded to levels detected in 19 years older euploid individuals. Sub-cohorts of DS without any known co-morbidities from different countries showed a similar result, eliminating DS- linked autoimmune diseases, frequent infections, or Alzheimer’s dementia as indirect causes of accelerated biological ageing. Importantly, no difference in slope of the curve relating IgG- glycan-age to chronological age was observed for any of the 3 analysed populations, discouraging the amplified-chromosomal-instability explanation. Remarkably, IgG-glycan profiles of a child with DS caused by a short segmental duplication of only 31 genes on chromosome-21 (DS-critical-region) had values like age-matched whole-chromosome-trisomy- 21 children, pointing to a causative contribution of one or more of the 31 genes. Conclusion: This shifts the paradigm from an (essentially untreateable) “amplified instability” mechanism, to a specific gene-overdose-driven cause of a progeria-like syndrome, opening possibilities for therapeutic amelioration strategies. We generated an induced pluripotent stem cell (iPSC) model of this child with partial trisomy 21, and editing experiments using CRISPR-Cas9 are underway in order to dissect the causative overdosed genes and mechanisms responsible for the accelerated ageing in DS.

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.

The goal was to explore the difference in N- glycosylation between euploid disomic (D21) and trisomic (T21) isogenic human induced pluripotent stem cells (iPSCs) and neural stem cells (NSCs) derived from person with mosaic Down syndrome (DS) trisomy of 21st chromosome.....