Down syndrome biological age is accelerated on average by 19 years, beginning in early childhood, independent of co-morbidities, and trisomy of Down-syndrome-critical-region is a sufficient trigger (CROSBI ID 721255)
Prilog sa skupa u zborniku | sažetak izlaganja sa skupa | međunarodna recenzija
Podaci o odgovornosti
Cindrić, Ana ; Vučković, Frano ; Alić, Ivan ; Gough, Gillian ; Koschut, David ; Borelli, Vincenzo ; Petrović, Dražen ; Bekavac, Ana ; Spector, Tim ; Mitrečić, Dinko ; Barišić, Ingeborg ; Thomas, Michael ; Strydom, Andre ; Rebillat, Anne-Sophie ; Franceschi, Claudio ; Lauc, Gordan ; Murray, Aoife ; Krištić, Jasminka ; Nižetić, Dean
engleski
Down syndrome biological age is accelerated on average by 19 years, beginning in early childhood, independent of co-morbidities, and trisomy of Down-syndrome-critical-region is a sufficient trigger
Abstract: 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, iPSC, Aging, IgG, Alzheimer
nije evidentirano
nije evidentirano
nije evidentirano
nije evidentirano
nije evidentirano
nije evidentirano
Podaci o prilogu
273-274.
2022.
objavljeno
Podaci o matičnoj publikaciji
T21RS 4th International conference Book of abstracts
Podaci o skupu
T21RS 4th International conference
predavanje
09.06.2022-12.06.2022
Long Beach (CA), Sjedinjene Američke Države