IQSEC2-Associated Intellectual Disability and Autism.

Nina S Levy,Orit Lache,Andrew P Levy,Reem Jada,Eli J Rogers,George K E Umanah

doi:10.3390/ijms20123038

Abstract

Mutations in IQSEC2 cause intellectual disability (ID), which is often accompanied by seizures and autism. A number of studies have shown that IQSEC2 is an abundant protein in excitatory synapses and plays an important role in neuronal development as well as synaptic plasticity. Here, we review neuronal IQSEC2 signaling with emphasis on those aspects likely to be involved in autism. IQSEC2 is normally bound to N-methyl-D-aspartate (NMDA)-type glutamate receptors via post synaptic density protein 95 (PSD-95). Activation of NMDA receptors results in calcium ion influx and binding to calmodulin present on the IQSEC2 IQ domain. Calcium/calmodulin induces a conformational change in IQSEC2 leading to activation of the SEC7 catalytic domain. GTP is exchanged for GDP on ADP ribosylation factor 6 (ARF6). Activated ARF6 promotes downregulation of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors through a c-jun N terminal kinase (JNK)-mediated pathway. NMDA receptors, AMPA receptors, and PSD-95 are all known to be adversely affected in autism. An IQSEC2 transgenic mouse carrying a constitutively active mutation (A350V) shows autistic features and reduced levels of surface AMPA receptor subunit GluA2. Sec7 activity and AMPA receptor recycling are presented as two targets, which may respond to drug treatment in IQSEC2-associated ID and autism.

Highlights

This review will summarize our current knowledge of the molecular basis of intellectual disability (ID) in individuals with mutations in the IQSEC2 gene and how compromised IQSEC2 function may be related to autism spectrum disorder (ASD)
We propose a model by which IQSEC2 acts in promoting neurotransmission highlighting aspects which may be disrupted by mutations in IQSEC2 resulting in ID and autism
This type of analysis found a large discrepancy between the predicted number of missense mutations (221) and those that were observed (86) [3]. This discrepancy may be due to the fact that missense mutations in regions other than the known functional domains do cause pathology, albeit less severe than that seen in IQSEC2-associated ID. Perhaps these cases are more mild forms of ID and or ASD with no epilepsy, which is the primary reason for doing exome sequencing of IQSEC2, yet not mild enough to be included in a normal group

Summary

Introduction

This review will summarize our current knowledge of the molecular basis of intellectual disability (ID) in individuals with mutations in the IQSEC2 gene and how compromised IQSEC2 function may be related to autism spectrum disorder (ASD). It is clear from clinical studies that autistic-like features are found in at least 25% of all IQSEC2 ID cases [1,2,3] This suggests a common biochemical pathway linking IQSEC2-associated ID and ASD. IQSEC2 is a guanine nucleotide exchange factor (GEF) that activates ADP ribosylation factor 6 (ARF6) and regulates proper membrane trafficking and synaptic structure and function in neurons. In this regard, ARF6 is important for maintaining the proper level of excitatory and inhibitory receptors essential for the normal learning process. We propose a model by which IQSEC2 acts in promoting neurotransmission highlighting aspects which may be disrupted by mutations in IQSEC2 resulting in ID and autism

Clinical Connection between IQSEC2 and ASD

IQSEC2 Structure and Function

IQSEC2 and Spine Formation

PSD-95

Findings

Glutamate Receptors