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

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dc.contributor University of Helsinki, HYKS erva en
dc.contributor University of Helsinki, Irma Järvelä / Principal Investigator en
dc.contributor.author Jackson, Matilda R.
dc.contributor.author Loring, Karagh E.
dc.contributor.author Homan, Claire C.
dc.contributor.author Thai, Monica H. N.
dc.contributor.author Maattanen, Laura
dc.contributor.author Arvio, Maria
dc.contributor.author Järvelä, Irma
dc.contributor.author Shaw, Marie
dc.contributor.author Gardner, Alison
dc.contributor.author Gecz, Jozef
dc.contributor.author Shoubridge, Cheryl
dc.date.accessioned 2019-11-07T14:40:01Z
dc.date.available 2019-11-07T14:40:01Z
dc.date.issued 2019-08
dc.identifier.citation 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 en
dc.identifier.issn 2575-1077
dc.identifier.other PURE: 127971645
dc.identifier.other PURE UUID: 5f2b5d67-cfad-47d1-9f46-188903f87706
dc.identifier.other WOS: 000484355500020
dc.identifier.other ORCID: /0000-0002-1770-6187/work/64323404
dc.identifier.uri http://hdl.handle.net/10138/306818
dc.description.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. en
dc.format.extent 18
dc.language.iso eng
dc.relation.ispartof Life Science Alliance
dc.rights en
dc.subject DE-NOVO MUTATIONS en
dc.subject NUCLEOTIDE EXCHANGE FACTOR en
dc.subject OF-FUNCTION MUTATIONS en
dc.subject INTELLECTUAL DISABILITY en
dc.subject POSTSYNAPTIC DENSITY en
dc.subject NEURAL INFORMATION en
dc.subject DNA METHYLATION en
dc.subject GENERATION en
dc.subject RECEPTORS en
dc.subject IQSEC2 en
dc.subject 3111 Biomedicine en
dc.title Heterozygous loss of function of IQSEC2/Iqsec2 leads to increased activated Arf6 and severe neurocognitive seizure phenotype in females en
dc.type Article
dc.description.version Peer reviewed
dc.identifier.doi https://doi.org/10.26508/lsa.201900386
dc.type.uri info:eu-repo/semantics/other
dc.type.uri info:eu-repo/semantics/publishedVersion
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