IQSEC2-Associated Intellectual Disability and Autism

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.

Keywords: AMPA receptors; NMDA receptors; autism; guanine nucleotide exchange factor; intellectual disability; synaptic plasticity.

Figure 1

Schematic diagram of the conserved domains found in the human IQSEC2 protein and the distribution of mutations found in IQSEC2 cases. The top panel (A) depicts the protein encoded by the most abundant transcript for human IQSEC2, which contains 1488 amino acids. The known conserved domains and motifs are shown in blue. They are: CC-coiled coil, IQ–calmodulin binding site, SEC7-catalytic domain for GTP/GDP exchange on ARF, PH-pleckstrin homology domain, PRM–proline-rich motif, and PDZ-PSD-95 binding motif. The bottom panel (B) shows the distribution of mutations found in the IQSEC2 gene (mutations were taken from Tables 2 and 3 from reference [3]) Missense mutations are shown in red; all other mutations (which include intragenic nonsense, duplication/truncation, in-frame deletions, and splicing variants) are shown in green. Hatched red bars show missense mutations associated with ASD. Hatched green bars show all other mutations associated with ASD. The positions of all mutations were arbitrarily chosen as the N terminal starting point. Mutations were considered to be associated with ASD if at least one member of the family was listed as having ASD traits or displaying autistic behavior.

Figure 2

Signal transduction pathway in wild type and A350V mutant IQSEC2. In the left panel (A), binding of glutamine to the NMDA receptor (pink shape) allows calcium ion influx (step 1). Binding of calcium to calmodulin present on IQSEC2 (light blue shape) causes a conformational change (step 2) in IQSEC2 resulting in activation of the SEC7 catalytic domain (step 3). GDP is exchanged for GTP on ARF6 (green shape), resulting in active ARF6 (step 4). Additional steps including JNK activation (purple shape) lead to endocytosis of AMPA receptors (step 5). In the right panel (B), the A350V mutant IQSEC2 is constitutively active (step 1) leading to constant activation of ARF6 and JNK, enhanced endocytosis of AMPA receptors (step 2), and decreased surface AMPA expression. (Reproduced from reference 17.)