Novel missense mutation A789V in IQSEC2 underlies X-linked intellectual disability in the MRX78 family

V M Kalscheuer; V M James; M L Himeiright; P Long; R Oegema; C Jensen; M Bienek; H Hu; S A Haas; M Topf; A J M Hoogeboom; K Harvey; R Walikonis; Robert J Harvey

doi:10.3389/fnmol.2015.00085

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Novel missense mutation A789V in IQSEC2 underlies X-linked intellectual disability in the MRX78 family

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Novel missense mutation A789V in IQSEC2 underlies X-linked intellectual disability in the MRX78 family

V M Kalscheuer, V M James, M L Himeiright, P Long, R Oegema, C Jensen, M Bienek, H Hu, S A Haas, M Topf, …

Frontiers in Molecular Neuroscience, Vol.8, 85

2016

DOI: https://doi.org/10.3389/fnmol.2015.00085

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Abstract

ArfGEF

BRAG1

IQ-ArfGEF

IQSEC2

MRX78

XLID

Disease gene discovery in neurodevelopmental disorders, including X-linked intellectual disability (XLID) has recently been accelerated by next-generation DNA sequencing approaches. To date, more than 100 human X chromosome genes involved in neuronal signaling pathways and networks implicated in cognitive function have been identified. Despite these advances, the mutations underlying disease in a large number of XLID families remained unresolved. We report the resolution of MRX78, a large family with six affected males and seven affected females, showing X-linked inheritance. Although a previous linkage study had mapped the locus to the short arm of chromosome X (Xp11.4-p11.23), this region contained too many candidate genes to be analyzed using conventional approaches. However, our X-chromosome exome resequencing, bioinformatics analysis and inheritance testing revealed a missense mutation (c.C2366T, p.A789V) in IQSEC2, encoding a neuronal GDP-GTP exchange factor for Arf family GTPases (ArfGEF) previously implicated in XLID. Molecular modeling of IQSEC2 revealed that the A789V substitution results in the insertion of a larger side-chain into a hydrophobic pocket in the catalytic Sec7 domain of IQSEC2. The A789V change is predicted to result in numerous clashes with adjacent amino acids and disruption of local folding of the Sec7 domain. Consistent with this finding, functional assays revealed that recombinant IQSEC2A789V was not able to catalyze GDP-GTP exchange on Arf6 as efficiently as wild-type IQSEC2. Taken together, these results strongly suggest that the A789V mutation in IQSEC2 is the underlying cause of XLID in the MRX78 family. © 2016 Kalscheuer, James, Himelright, Long, Oegema, Jensen, Bienek, Hu, Haas, Topf, Hoogeboom, Harvey, Walikonis and Harvey.

Details

Title: Novel missense mutation A789V in IQSEC2 underlies X-linked intellectual disability in the MRX78 family
Authors: V M Kalscheuer (Author) - Max Planck Institute for Molecular Genetics, Germany
V M James (Author) - University College London, United Kingdom
M L Himeiright (Author) - University of Connecticut, United States
P Long (Author) - University College London, United Kingdom
R Oegema (Author) - Erasmus MC University Medical Center Rotterdam, Netherlands
C Jensen (Author) - Max Planck Institute for Molecular Genetics, Germany
M Bienek (Author) - Max Planck Institute for Molecular Genetics, Germany
H Hu (Author) - Max Planck Institute for Molecular Genetics, Germany
S A Haas (Author) - Max Planck Institute for Molecular Genetics, Germany
M Topf (Author) - Birkbeck College, United Kingdom
A J M Hoogeboom (Author) - Erasmus MC University Medical Center Rotterdam, Netherlands
K Harvey (Author) - University College London, United Kingdom
R Walikonis (Author) - University of Connecticut, United States
Robert J Harvey (Author) - University College London, United Kingdom
Publication details: Frontiers in Molecular Neuroscience, Vol.8, 85; 10
Publisher: Frontiers Research Foundation
Date published: 2016
DOI: 10.3389/fnmol.2015.00085
ISSN: 1662-5099
Copyright note: Copyright © 2016 Kalscheuer, James, Himelright, Long, Oegema, Jensen, Bienek, Hu, Haas, Topf, Hoogeboom, Harvey, Walikonis 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: 99451025602621
Output Type: Journal article

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