Missense mutation R338W in ARHGEF9 in a family with X-linked intellectual disability with variable macrocephaly and macro-orchidism

P Long; M M May; V M James; S Grannò; J P Johnson; P Tarpey; R E Stevenson; K Harvey; C E Schwartz; Robert J Harvey

doi:10.3389/fnmol.2015.00083

Back

Missense mutation R338W in ARHGEF9 in a family with X-linked intellectual disability with variable macrocephaly and macro-orchidism

Journal article

Open access

Peer reviewed

Missense mutation R338W in ARHGEF9 in a family with X-linked intellectual disability with variable macrocephaly and macro-orchidism

P Long, M M May, V M James, S Grannò, J P Johnson, P Tarpey, R E Stevenson, K Harvey, C E Schwartz and Robert J Harvey

Frontiers in Molecular Neuroscience, Vol.8, 83

2016

DOI: https://doi.org/10.3389/fnmol.2015.00083

Files and links (2)

pdf

PDF - Published Version (Open Access)854.74 kBDownload View

Published VersionPDF - Published Version (Open Access)CC BY V4.0, Open Access

url

https://doi.org/10.3389/fnmol.2015.00083View

Published Version

Abstract

ARHGEF9

collybistin

gephyrin

PH domain

XLID

Non-syndromal X-linked intellectual disability (NS-XLID) represents a broad group of clinical disorders in which ID is the only clinically consistent manifestation. Although in many cases either chromosomal linkage data or knowledge of the >100 existing XLID genes has assisted mutation discovery, the underlying cause of disease remains unresolved in many families. We report the resolution of a large family (K8010) with NS-XLID, with variable macrocephaly and macro-orchidism. Although a previous linkage study had mapped the locus to Xq12-q21, this region contained too many candidate genes to be analyzed using conventional approaches. However, X-chromosome exome sequencing, bioinformatics analysis and segregation analysis revealed a novel missense mutation (c.1012C>T; p.R338W) in ARHGEF9. This gene encodes collybistin (CB), a neuronal GDP-GTP exchange factor previously implicated in several cases of XLID, as well as clustering of gephyrin and GABAA receptors at inhibitory synapses. Molecular modeling of the CB R338W substitution revealed that this change results in the substitution of a long electropositive side-chain with a large non-charged hydrophobic side-chain. The R338W change is predicted to result in clashes with adjacent amino acids (K363 and N335) and disruption of electrostatic potential and local folding of the PH domain, which is known to bind phosphatidylinositol-3-phosphate (PI3P/PtdIns-3-P). Consistent with this finding, functional assays revealed that recombinant CB CB2sH3-R338W was deficient in PI3P binding and was not able to translocate EGFP-gephyrin to submembrane microaggregates in an in vitro clustering assay. Taken together, these results suggest that the R338W mutation in ARHGEF9 is the underlying cause of NS-XLID in this family. © 2016 Long, May, James, Grannó, Johnson, Tarpey, Stevenson, Harvey, Schwartz and Harvey.

Details

Title: Missense mutation R338W in ARHGEF9 in a family with X-linked intellectual disability with variable macrocephaly and macro-orchidism
Authors: P Long (Author) - University College London, United Kingdom
M M May (Author) - Greenwood Genetic Center, United States
V M James (Author) - University College London, United Kingdom
S Grannò (Author) - University College London, United Kingdom
J P Johnson (Author) - Shodair Children's Hospital, United States
P Tarpey (Author) - Wellcome Trust Sanger Institute, United Kingdom
R E Stevenson (Author) - Greenwood Genetic Center, United States
K Harvey (Author) - University College London, United Kingdom
C E Schwartz (Author) - Greenwood Genetic Center, United States
Robert J Harvey (Author) - University College London, United Kingdom
Publication details: Frontiers in Molecular Neuroscience, Vol.8, 83; 8
Publisher: Frontiers Research Foundation
Date published: 2016
DOI: 10.3389/fnmol.2015.00083
ISSN: 1662-5099
Copyright note: Copyright © 2016 Long, May, James, Grannò, Johnson, Tarpey, Stevenson, Harvey, Schwartz and Harvey. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Organisation Unit: School of Health; University of the Sunshine Coast, Queensland; School of Health and Sport Sciences - Legacy; Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy
Language: English
Record Identifier: 99451014202621
Output Type: Journal article

Metrics

30 File views/ downloads

690 Record Views

23 Times Cited - Web of Science

See more details

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Collaboration types: Domestic collaboration; International collaboration
Web Of Science research areas: Neurosciences

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

Source: InCites