Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/106202
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Type: Journal article
Title: Incorrect dosage of IQSEC2, a known intellectual disability and epilepsy gene, disrupts dendritic spine morphogenesis
Author: Hinze, S.
Jackson, M.
Lie, S.
Jolly, L.
Field, M.
Barry, S.
Harvey, R.
Shoubridge, C.
Citation: Translational Psychiatry, 2017; 7(5):e1110-1-e-1110-11
Publisher: Nature Publishing Group
Issue Date: 2017
ISSN: 2158-3188
2158-3188
Statement of
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SJ Hinze, MR Jackson, S Lie, L Jolly, M Field, SC Barry, RJ Harvey and C Shoubridge
Abstract: There is considerable genetic and phenotypic heterogeneity associated with intellectual disability (ID), specific learning disabilities, attention-deficit hyperactivity disorder, autism and epilepsy. The intelligence quotient (IQ) motif and SEC7 domain containing protein 2 gene (IQSEC2) is located on the X-chromosome and harbors mutations that contribute to non-syndromic ID with and without early-onset seizure phenotypes in both sexes. Although IQ and Sec7 domain mutations lead to partial loss of IQSEC2 enzymatic activity, the in vivo pathogenesis resulting from these mutations is not known. Here we reveal that IQSEC2 has a key role in dendritic spine morphology. Partial loss-of-function mutations were modeled using a lentiviral short hairpin RNA (shRNA) approach, which achieved a 57% knockdown of Iqsec2 expression in primary hippocampal cell cultures from mice. Investigating gross morphological parameters after 8 days of in vitro culture (8DIV) identified a 32% reduction in primary axon length, in contrast to a 27% and 31% increase in the number and complexity of dendrites protruding from the cell body, respectively. This increase in dendritic complexity and spread was carried through dendritic spine development, with a 34% increase in the number of protrusions per dendritic segment compared with controls at 15DIV. Although the number of dendritic spines had normalized by 21DIV, a reduction was noted in the number of immature spines. In contrast, when modeling increased dosage, overexpression of wild-type IQSEC2 led to neurons with shorter axons that were more compact and displayed simpler dendritic branching. Disturbances to dendritic morphology due to knockdown of Iqsec2 were recapitulated in neurons from Iqsec2 knockout mice generated in our laboratory using CRISPR/Cas9 technology. These observations provide evidence of dosage sensitivity for IQSEC2, which normally escapes X-inactivation in females, and links these disturbances in expression to alterations in the morphology of developing neurons.
Keywords: Hippocampus; Neurons; Dendrites; Dendritic Spines; Animals; Mice, Knockout; Mice; Epilepsy; Guanine Nucleotide Exchange Factors; Nerve Tissue Proteins; RNA, Small Interfering; Phenotype; Mutation; Female; Male; Neurogenesis; Intellectual Disability
Rights: © The Author(s) 2017 This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
RMID: 0030069226
DOI: 10.1038/tp.2017.81
Grant ID: http://purl.org/au-research/grants/nhmrc/1006586
http://purl.org/au-research/grants/arc/FT120100086
Appears in Collections:Paediatrics publications

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