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Human neurons carrying FMR1 unmethylated full mutations require large CGG repeat expansions for silencing and display neurodegenerative features

Brykczynska Kunzmann, Urszula and Vrieseling Pecho, Eline and Thiemeyer, Anke and Klein, Jessica and Fruh, Isabelle and Doll, Thierry and Manneville, Carole and Iazeolla, Mariavittoria and Beibel, Martin and Roma, Guglielmo and Naumann, Ulrike and Kelley, Nicholas and Oakeley, Edward James and Mueller, Matthias and Gomez-Mancilla, Baltazar and Buehler, Marc and Tabolacci, Elisabetta and Chiruazzi, Pietro and Neri, Giovanni and Bouwmeester, Antonius and Di Giorgio, Francesco and Fodor, Barna (2016) Human neurons carrying FMR1 unmethylated full mutations require large CGG repeat expansions for silencing and display neurodegenerative features. Cell Stem Cell.

Abstract

In Fragile X Syndrome (FXS), unmethylated full mutation (UFM) individuals carry a CGG expansion greater than 200 repeats in the FMR1 gene but lack the disease causing DNA methylation mediated silencing. Here, we show that hypomethylation of the FMR1 promoter is maintained in induced pluripotent stem cells (iPSCs) derived from two UFM individuals. However, we identify a subset of iPSC clones with large CGG expansions that silence FMR1. Furthermore, we demonstrate that de-novo silencing occurs upon expansion of CGG repeats. The silencing status of FMR1 is stable during neuronal differentiation. This indicates that UFM stem cells do not undergo developmental silencing as described for FXS. We also show that the expression of large unmethylated CGG repeats has direct phenotypic consequences resulting in neurodegenerative features. Our data suggest that UFM individuals do not lack the ability to silence FMR1 but require a higher CGG repeat size than the one described for FXS patients.

Item Type: Article
Keywords: Fragile X Syndrome, Fragile X-Associated Tremor/Ataxia Syndrome, induced pluripotent stem cell, DNA methylation, neuron, CGG repeat
Date Deposited: 29 Apr 2016 23:45
Last Modified: 29 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/26680

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