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Cell Rep DOI:10.1016/j.celrep.2022.111312

Molecular convergence between Down syndrome and fragile X syndrome identified using human pluripotent stem cell models.

Publication TypeJournal Article
Year of Publication2022
AuthorsSusco, SG, Ghosh, S, Mazzucato, P, Angelini, G, Beccard, A, Barrera, V, Berryer, MH, Messana, A, Lam, D, Hazelbaker, DZ, Barrett, LE
JournalCell Rep
Volume40
Issue10
Pages111312
Date Published2022 Sep 06
ISSN2211-1247
Abstract

Down syndrome (DS), driven by an extra copy of chromosome 21 (HSA21), and fragile X syndrome (FXS), driven by loss of the RNA-binding protein FMRP, are two common genetic causes of intellectual disability and autism. Based upon the number of DS-implicated transcripts bound by FMRP, we hypothesize that DS and FXS may share underlying mechanisms. Comparing DS and FXS human pluripotent stem cell (hPSC) and glutamatergic neuron models, we identify increased protein expression of select targets and overlapping transcriptional perturbations. Moreover, acute upregulation of endogenous FMRP in DS patient cells using CRISPRa is sufficient to significantly reduce expression levels of candidate proteins and reverse 40% of global transcriptional perturbations. These results pinpoint specific molecular perturbations shared between DS and FXS that can be leveraged as a strategy for target prioritization; they also provide evidence for the functional relevance of previous associations between FMRP targets and disease-implicated genes.

DOI10.1016/j.celrep.2022.111312
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/36070702?dopt=Abstract

Alternate JournalCell Rep
PubMed ID36070702