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

Francisco Bustos, Anna Segarra Fas, Viduth K. Chaugule, Lennart Brandenburg, Emma Branigan, Rachel Toth, Thomas Macartney, Axel Knebel, Ronald Hay, Helen Walden, Greg Findlay (Lead / Corresponding author)

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Abstract

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 developmentallyrelevant substrates. XLID mutants disrupt distinct RNF12 functional modules, either by 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.
Original languageEnglish
Pages (from-to)1599-1611
Number of pages13
JournalCell Reports
Volume23
Issue number6
DOIs
Publication statusPublished - 8 May 2018

Fingerprint

Ubiquitin-Protein Ligases
Stem cells
Intellectual Disability
Mutation
Genes
Nucleic Acid Regulatory Sequences
Ubiquitin
Neural Stem Cells
Catalyst activity
Substrates
Ubiquitination
Medical Genetics
Embryonic Stem Cells
Catalytic Domain
Maintenance

Keywords

  • E3 ubiquitin ligase
  • RNF12/RLIM
  • X-linked intellectual disability
  • embryonic stem cells
  • intellectual disability
  • neural differentiation
  • proteasomal degradation
  • protein ubiquitylation
  • ubiquitin

Cite this

@article{d25bbfedc65b4d66aa75e9ac9d39637c,
title = "RNF12 X-linked intellectual disability mutations disrupt E3 ligase activity and neural differentiation",
abstract = "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 developmentallyrelevant substrates. XLID mutants disrupt distinct RNF12 functional modules, either by 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.",
keywords = "E3 ubiquitin ligase, RNF12/RLIM, X-linked intellectual disability, embryonic stem cells, intellectual disability, neural differentiation, proteasomal degradation, protein ubiquitylation, ubiquitin",
author = "Francisco Bustos and {Segarra Fas}, Anna and Chaugule, {Viduth K.} and Lennart Brandenburg and Emma Branigan and Rachel Toth and Thomas Macartney and Axel Knebel and Ronald Hay and Helen Walden and Greg Findlay",
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RNF12 X-linked intellectual disability mutations disrupt E3 ligase activity and neural differentiation. / Bustos, Francisco; Segarra Fas, Anna; Chaugule, Viduth K.; Brandenburg, Lennart; Branigan, Emma; Toth, Rachel; Macartney, Thomas; Knebel, Axel; Hay, Ronald; Walden, Helen; Findlay, Greg (Lead / Corresponding author).

In: Cell Reports, Vol. 23, No. 6, 08.05.2018, p. 1599-1611.

Research output: Contribution to journalArticle

TY - JOUR

T1 - RNF12 X-linked intellectual disability mutations disrupt E3 ligase activity and neural differentiation

AU - Bustos, Francisco

AU - Segarra Fas, Anna

AU - Chaugule, Viduth K.

AU - Brandenburg, Lennart

AU - Branigan, Emma

AU - Toth, Rachel

AU - Macartney, Thomas

AU - Knebel, Axel

AU - Hay, Ronald

AU - Walden, Helen

AU - Findlay, Greg

N1 - 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.

PY - 2018/5/8

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N2 - 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 developmentallyrelevant substrates. XLID mutants disrupt distinct RNF12 functional modules, either by 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.

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