RT Journal Article
SR Electronic
T1 Heterozygous loss of function of <em>IQSEC2</em>/<em>Iqsec2</em> leads to increased activated Arf6 and severe neurocognitive seizure phenotype in females
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900386
DO 10.26508/lsa.201900386
VO 2
IS 4
A1 Matilda R Jackson
A1 Karagh E Loring
A1 Claire C Homan
A1 Monica HN Thai
A1 Laura Määttänen
A1 Maria Arvio
A1 Irma Jarvela
A1 Marie Shaw
A1 Alison Gardner
A1 Jozef Gecz
A1 Cheryl Shoubridge
YR 2019
UL https://www.life-science-alliance.org/content/2/4/e201900386.abstract
AB 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 &gt; 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.