RNF12 X-linked intellectual disability mutations disrupt E3 ligase activity and neural differentiation.

Bustos, F. et al. (2018) RNF12 X-linked intellectual disability mutations disrupt E3 ligase activity and neural differentiation. Cell Reports, 23(6), pp. 1599-1611. (doi: 10.1016/j.celrep.2018.04.022) (PMID:29742418) (PMCID:PMC5976579)

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X-linked intellectual disability (XLID) is a heterogeneous syndrome affecting mainly males. Human genetics has identified >100 XLID genes, although the molecular and developmental mechanisms underpinning this disorder remain unclear. Here, we employ an embryonic stem cell model to explore developmental functions of a recently identified XLID gene, the RNF12/RLIM E3 ubiquitin ligase. We show that RNF12 catalytic activity is required for proper stem cell maintenance and neural differentiation, and this is disrupted by patient-associated XLID mutation. We further demonstrate that RNF12 XLID mutations specifically impair ubiquitylation of developmentally relevant substrates. XLID mutants disrupt distinct RNF12 functional modules by either inactivating the catalytic RING domain or interfering with a distal regulatory region required for efficient ubiquitin transfer. Our data thereby uncover a key function for RNF12 E3 ubiquitin ligase activity in stem cell and neural development and identify mechanisms by which this is disrupted in intellectual disability.

Item Type:Articles
Additional Information:This work was supported by a Medical Research Council New Investigator Award (MR/N000609/1) and a Tenovus Scotland research grant (T15/11) to G.M.F.
Keywords:E3 ubiquitin ligase, RNF12/RLIM, X-linked intellectual disability, embryonic stem cells, intellectual disability, neural differentiation, proteasomal degradation, protein ubiquitylation, ubiquitin
Glasgow Author(s) Enlighten ID:Chaugule, Dr Viduth and Walden, Professor Helen
Authors: Bustos, F., Segarra-Fas, A., Chaugule, V. K., Brandenburg, L., Branigan, E., Toth, R., Macartney, T., Knebel, A., Hay, R. T., Walden, H., and Findlay, G. M.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Cell Reports
ISSN (Online):2211-1247
Published Online:25 May 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Cell Reports 23(6):1599-1611
Publisher Policy:Reproduced under a Creative Commons License

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