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Front Mol Neurosci. 2016 Jan 11;8:85. doi: 10.3389/fnmol.2015.00085. eCollection 2015.

Novel Missense Mutation A789V in IQSEC2 Underlies X-Linked Intellectual Disability in the MRX78 Family.

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Department of Human Molecular Genetics, Max Planck Institute for Molecular GeneticsBerlin, Germany; Research Group Development and Disease, Max Planck Institute for Molecular GeneticsBerlin, Germany.
Department of Pharmacology, UCL School of Pharmacy London, UK.
Department of Physiology and Neurobiology, University of Connecticut Storrs, CT, USA.
Department of Clinical Genetics, Erasmus MC University Medical Center Rotterdam Rotterdam, Netherlands.
Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics Berlin, Germany.
Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics Berlin, Germany.
Department of Biological Sciences, Institute for Structural and Molecular Biology, Birkbeck College London, UK.


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 IQSEC2(A789V) 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.



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