English
 
User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  Mutation p.R356Q in the Collybistin Phosphoinositide Binding Site Is Associated With Mild Intellectual Disability

Chiou, T. T., Long, P., Schumann-Gillett, A., Kanamarlapudi, V., Haas, S. A., Harvey, K., et al. (2019). Mutation p.R356Q in the Collybistin Phosphoinositide Binding Site Is Associated With Mild Intellectual Disability. Frontiers in Molecular Neuroscience, 12: 12:60. doi:10.3389/fnmol.2019.00060.

Item is

Basic

show hide
Item Permalink: http://hdl.handle.net/21.11116/0000-0006-09F8-9 Version Permalink: http://hdl.handle.net/21.11116/0000-0006-09F9-8
Genre: Journal Article

Files

show Files
hide Files
:
Chiou_2019.pdf (Publisher version), 8MB
Name:
Chiou_2019.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
© 2019 Chiou et al

Locators

show
hide
Description:
-

Creators

show
hide
 Creators:
Chiou, T. T., Author
Long, P., Author
Schumann-Gillett, A., Author
Kanamarlapudi, V., Author
Haas, S. A.1, Author              
Harvey, K., Author
O'Mara, M. L., Author
De Blas, A. L., Author
Kalscheuer, V. M.2, Author              
Harvey, R. J., Author
Affiliations:
1Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433547              
2Chromosome Rearrangements and Disease (Vera Kalscheuer), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385702              

Content

show
hide
Free keywords: ARHGEF9; Collybistin; Gephyrin; PH domain; PI3P; XLID
 Abstract: The recruitment of inhibitory GABAA receptors to neuronal synapses requires a complex interplay between receptors, neuroligins, the scaffolding protein gephyrin and the GDP-GTP exchange factor collybistin (CB). Collybistin is regulated by protein-protein interactions at the N-terminal SH3 domain, which can bind neuroligins 2/4 and the GABAAR alpha2 subunit. Collybistin also harbors a RhoGEF domain which mediates interactions with gephyrin and catalyzes GDP-GTP exchange on Cdc42. Lastly, collybistin has a pleckstrin homology (PH) domain, which binds phosphoinositides, such as phosphatidylinositol 3-phosphate (PI3P/PtdIns3P) and phosphatidylinositol 4-monophosphate (PI4P/PtdIns4P). PI3P located in early/sorting endosomes has recently been shown to regulate the postsynaptic clustering of gephyrin and GABAA receptors and consequently the strength of inhibitory synapses in cultured hippocampal neurons. This process is disrupted by mutations in the collybistin gene (ARHGEF9), which cause X-linked intellectual disability (XLID) by a variety of mechanisms converging on disrupted gephyrin and GABAA receptor clustering at central synapses. Here we report a novel missense mutation (chrX:62875607C>T, p.R356Q) in ARHGEF9 that affects one of the two paired arginine residues in the PH domain that were predicted to be vital for binding phosphoinositides. Functional assays revealed that recombinant collybistin CB3SH3- (R356Q) was deficient in PI3P binding and was not able to translocate EGFP-gephyrin to submembrane microaggregates in an in vitro clustering assay. Expression of the PI3P-binding mutants CB3SH3- (R356Q) and CB3SH3- (R356N/R357N) in cultured hippocampal neurones revealed that the mutant proteins did not accumulate at inhibitory synapses, but instead resulted in a clear decrease in the overall number of synaptic gephyrin clusters compared to controls. Molecular dynamics simulations suggest that the p.R356Q substitution influences PI3P binding by altering the range of structural conformations adopted by collybistin. Taken together, these results suggest that the p.R356Q mutation in ARHGEF9 is the underlying cause of XLID in the probands, disrupting gephyrin clustering at inhibitory GABAergic synapses via loss of collybistin PH domain phosphoinositide binding.

Details

show
hide
Language(s): eng - English
 Dates: 2019-02-192019-03-12
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.3389/fnmol.2019.00060
ISSN: 1662-5099
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Frontiers in Molecular Neuroscience
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: Lausanne, Switzerland : Frontiers Research Foundation
Pages: - Volume / Issue: 12 Sequence Number: 12:60 Start / End Page: - Identifier: ISSN: 1662-5099
CoNE: https://pure.mpg.de/cone/journals/resource/1662-5099