University of Oulu

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 Heterozygous loss of function of IQSEC2. Life Science Alliance Aug 2019, 2 (4) e201900386; DOI: 10.26508/lsa.201900386

Heterozygous loss of function of IQSEC2/Iqsec2 leads to increased activated Arf6 and severe neurocognitive seizure phenotype in females

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Author: Jackson, Matilda R.1,2; Loring, Karagh E.1,2; Homan, Claire C.2;
Organizations: 1Intellectual Disability Research, Adelaide Medical School, The University of Adelaide, Adelaide, Australia
2Department of Paediatrics, Robinson Research Institute, University of Adelaide, Adelaide, Australia
3Department of Child Neurology, Turku University Hospital, Turku, Finland
4Joint Authority for Päijät-Häme Social and Health Care, Lahti, Finland
5PEDEGO, Oulu University Hospital, Oulu, Finland
6Department of Medical Genetics, University of Helsinki, Helsinki, Finland
7South Australian Health and Medical Research Institute, Adelaide, Australia
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.7 MB)
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Language: English
Published: Life Science Alliance, 2019
Publish Date: 2020-03-27


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.

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Series: Life science alliance
ISSN: 2575-1077
ISSN-E: 2575-1077
ISSN-L: 2575-1077
Volume: 2
Issue: 4
Article number: e201900386
DOI: 10.26508/lsa.201900386
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: This research undertaken by the Intellectual Disability Research program in the Adelaide Medical School, University of Adelaide, Australia, was funded by the Australian National Health and Medical Research Council (Grant No 1063025) and Channel 7 Children’s Research Foundation (Grant 161263). C Shoubridge was supported by the Australian Research Council (Future Fellowship FT120100086).
Copyright information: © 2019 Jackson et al. article is available under a Creative Commons License (Attribution 4.0 International, as described at