Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/123452
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Type: Journal article
Title: Heterozygous loss of function of IQSEC2/Iqsec2 leads to increased activated Arf6 and severe neurocognitive seizure phenotype in females
Author: Jackson, M.
Loring, K.
Homan, C.
Thai, M.
Määttänen, L.
Arvio, M.
Jarvela, I.
Shaw, M.
Gardner, A.
Gecz, J.
Shoubridge, C.
Citation: Life Science Alliance, 2019; 2(4):e201900386-1-e201900386-18
Publisher: Life Science Alliance
Issue Date: 2019
ISSN: 2575-1077
2575-1077
Statement of
Responsibility: 
Matilda R Jackson, Karagh E Loring, Claire C Homan, Monica HN Thai, Laura Määttänen, Maria Arvio, Irma Jarvela, Marie Shaw, Alison Gardner, Jozef Gecz, Cheryl Shoubridge
Abstract: Clinical presentations of mutations in the IQSEC2 gene on the X-chromosome initially implicated to cause non-syndromic intellectual disability (ID) in males have expanded to include early onset seizures in males as well as in females. The molecular pathogenesis is not well understood, nor the mechanisms driving disease expression in heterozygous females. Using a CRISPR/Cas9-edited Iqsec2 KO mouse model, we confirm the loss of Iqsec2 mRNA expression and lack of Iqsec2 protein within the brain of both founder and progeny mice. Both male (52%) and female (46%) Iqsec2 KO mice present with frequent and recurrent seizures. Focusing on Iqsec2 KO heterozygous female mice, we demonstrate increased hyperactivity, altered anxiety and fear responses, decreased social interactions, delayed learning capacity and decreased memory retention/novel recognition, recapitulating psychiatric issues, autistic-like features, and cognitive deficits present in female patients with loss-of-function IQSEC2 variants. Despite Iqsec2 normally acting to activate Arf6 substrate, we demonstrate that mice modelling the loss of Iqsec2 function present with increased levels of activated Arf6. We contend that loss of Iqsec2 function leads to altered regulation of activated Arf6-mediated responses to synaptic signalling and immature synaptic networks. We highlight the importance of IQSEC2 function for females by reporting a novel nonsense variant c.566C > A, p.(S189*) in an elderly female patient with profound intellectual disability, generalised seizures, and behavioural disturbances. Our human and mouse data reaffirm IQSEC2 as another disease gene with an unexpected X-chromosome heterozygous female phenotype. Our Iqsec2 mouse model recapitulates the phenotypes observed in human patients despite the differences in the IQSEC2/Iqsec2 gene X-chromosome inactivation between the species.
Keywords: Brain; Animals; Mice, Inbred C57BL; Mice, Knockout; Humans; Mice; Seizures; Disease Models, Animal; ADP-Ribosylation Factors; Guanine Nucleotide Exchange Factors; Nerve Tissue Proteins; Pedigree; Autistic Disorder; Mutation; Loss of Heterozygosity; Aged; Middle Aged; Female; Male; Intellectual Disability
Rights: © 2019 Jackson et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
RMID: 0030133440
DOI: 10.26508/lsa.201900386
Grant ID: http://purl.org/au-research/grants/nhmrc/1063025
http://purl.org/au-research/grants/arc/FT120100086
Appears in Collections:Medicine publications

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