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

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Jackson , M R , Loring , K E , Homan , C C , Thai , M H N , Maattanen , L , Arvio , M , Järvelä , I , Shaw , M , Gardner , A , Gecz , J & Shoubridge , C 2019 , ' Heterozygous loss of function of IQSEC2/Iqsec2 leads to increased activated Arf6 and severe neurocognitive seizure phenotype in females ' , Life Science Alliance , vol. 2 , no. 4 , 201900386 . https://doi.org/10.26508/lsa.201900386

Title: Heterozygous loss of function of IQSEC2/Iqsec2 leads to increased activated Arf6 and severe neurocognitive seizure phenotype in females
Author: Jackson, Matilda R.; Loring, Karagh E.; Homan, Claire C.; Thai, Monica H. N.; Maattanen, Laura; Arvio, Maria; Järvelä, Irma; Shaw, Marie; Gardner, Alison; Gecz, Jozef; Shoubridge, Cheryl
Contributor: University of Helsinki, HYKS erva
University of Helsinki, Irma Järvelä / Principal Investigator
Date: 2019-08
Number of pages: 18
Belongs to series: Life Science Alliance
ISSN: 2575-1077
URI: http://hdl.handle.net/10138/306818
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.
Subject: DE-NOVO MUTATIONS
NUCLEOTIDE EXCHANGE FACTOR
OF-FUNCTION MUTATIONS
INTELLECTUAL DISABILITY
POSTSYNAPTIC DENSITY
NEURAL INFORMATION
DNA METHYLATION
GENERATION
RECEPTORS
IQSEC2
3111 Biomedicine
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