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

Kalscheuer, V. M., James, V. M., Himelright, M. L., Long, P., Oegema, R., Jensen, C., et al. (2016). Novel Missense Mutation A789V in IQSEC2 Underlies X-Linked Intellectual Disability in the MRX78 Family. Frontiers in Molecular Neuroscience, 8: 8:85. doi:10.3389/fnmol.2015.00085.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002E-1D80-9 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002E-1D81-7
Genre: Journal Article

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 Creators:
Kalscheuer, V. M.1, Author              
James, V. M., Author
Himelright, M. L., Author
Long, P., Author
Oegema, R., Author
Jensen, C., Author
Bienek, M.2, Author              
Hu, H.2, Author              
Haas, S. A.3, Author              
Topf, M., Author
Hoogeboom, A. J., Author
Harvey, K., Author
Walikonis, R., Author
Harvey, R. J., Author
Affiliations:
1Chromosome Rearrangements and Disease (Vera Kalscheuer), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385702              
2Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433549              
3Gene Structure and Array Design (Stefan Haas), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479640              

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Free keywords: ArfGEF Brag1 IQ-ArfGEF Iqsec2 Mrx78 Xlid
 Abstract: 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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Language(s): eng - English
 Dates: 2016-01-11
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.3389/fnmol.2015.00085
ISSN: 1662-5099
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Title: Frontiers in Molecular Neuroscience
Source Genre: Journal
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Publ. Info: Lausanne, Switzerland : Frontiers Research Foundation
Pages: - Volume / Issue: 8 Sequence Number: 8:85 Start / End Page: - Identifier: ISSN: 1662-5099
CoNE: /journals/resource/1662-5099