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

Frontiers in Molecular Neuroscience
Vera M KalscheuerRobert J Harvey

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 predi...Continue Reading

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Citations

Jun 1, 2016·Frontiers in Synaptic Neuroscience·Anna FassioFabio Benfenati
Oct 16, 2016·Small GTPases·Ryan S D'Souza, James E Casanova
Sep 22, 2016·Molecular Genetics & Genomic Medicine·Carolien G F de KovelBobby P C Koeleman
Mar 16, 2017·European Journal of Human Genetics : EJHG·Lisa J EwansCheryl Shoubridge
Aug 18, 2017·American Journal of Medical Genetics. Part a·Benjamin M HelmSamantha A Schrier Vergano
Sep 13, 2018·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Cyril MignotChristel Depienne
Oct 31, 2020·Journal of Neurochemistry·Dušica BriševacHans-Christian Kornau

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Methods Mentioned

BETA
GTPase
pull-down
GTPases
pulldown
biopsy
exome sequencing

Software Mentioned

SplazerS
snpStore
PolyPhen
RaptorX
GENCODYS
LOMETS
Medical Resequencing Analysis Pipeline ( MERAP
SIFT
Chimera
HHPred

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