An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors

Abstract

We have recently described an A350V mutation in IQSEC2 associated with intellectual disability, autism and epilepsy. We sought to understand the molecular pathophysiology of this mutation with the goal of developing targets for drug intervention. We demonstrate here that the A350V mutation results in interference with the binding of apocalmodulin to the IQ domain of IQSEC2. We further demonstrate that this mutation results in constitutive activation of the guanine nucleotide exchange factor (GEF) activity of IQSEC2 resulting in increased production of the active form of Arf6. In a CRISPR generated mouse model of the A350V IQSEC2 mutation, we demonstrate that the surface expression of GluA2 AMPA receptors in mouse hippocampal tissue was significantly reduced in A350V IQSEC2 mutant mice compared to wild type IQSEC2 mice and that there is a significant reduction in basal synaptic transmission in the hippocampus of A350V IQSEC2 mice compared to wild type IQSEC2 mice. Finally, the A350V IQSEC2 mice demonstrated increased activity, abnormal social behavior and learning as compared to wild type IQSEC2 mice. These findings suggest a model of how the A350V mutation in IQSEC2 may mediate disease with implications for targets for drug therapy. These studies provide a paradigm for a personalized approach to precision therapy for a disease that heretofore has no therapy.

Non‐syndromic X linked intellectual disability: Current knowledge in light of the recent advances in molecular and functional studies

“…The four families showed moderate to severe ID in affected males, seizures, autistic traits and psychiatric problems were also reported in an inconsistent manner. To date, more than 70 mutations have been reported in IQSEC2 leading to moderate to severe intellectual disability with variable seizures and autistic traits . Although this gene has been included in Figure as possibly responsible for syndromic forms according to Neri et al, this review has failed in finding syndromic forms.…”

“…IQSEC2 has been shown to bind calmodulin in a calcium dependent manner through the IQ domain. Rogers et al showed that missense mutations on the IQ domain lead to impaired calmodulin binding, increase IQSEC2 GEF activity and lead to decreased AMPA receptor in brains of mice. These mice show abnormal behavioral phenotypes with increased locomotion, abnormal social interactions and decreased learning.…”

Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability

“…Mutations in IQSEC2 were first described in families with non-syndromic XLID [43] and affected males showed moderate to severe intellectual disability, seizures, autistic traits, and behavioral disturbances as our patients do. To date, more than 70 mutations have been reported in IQSEC2 leading to a similar phenotype [44,45]. Some of these mutations are clustered in functional domains like IQ and Sec7 domains, which have been demonstrated to impair GEF activity [44,46,47].…”

“…However, as it is a missense variant and no other pathogenic missense variants have been reported at the CC domain, functional studies would be needed to establish its pathogenicity and understand its disease mechanism. phenotype [44,45]. Some of these mutations are clustered in functional domains like IQ and Sec7 domains, which have been demonstrated to impair GEF activity [44,46,47].…”

“…Intellectual disability (ID) is the most common neurodevelopmental disorder with a worldwide prevalence of about 1% [1,2] and is defined by impaired cognitive functioning and adaptive behavior arising before the age of 18 [3]. Its severity is usually measured by the intelligence quotient (IQ) score and classified as mild (IQ [55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70], moderate (IQ [40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55], severe (IQ [25][26][27][28][29][30][31][32][33][34][35][36][37][38]…”