IQSEC2-Associated Intellectual Disability and Autism

• Published in: International journal of molecular sciences Vol. 20; no. 12; p. 3038
• Main Authors: Levy, Nina S, Umanah, George K E, Rogers, Eli J, Jada, Reem, Lache, Orit, Levy, Andrew P
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21-06-2019; MDPI
• Subjects: ADP-ribosylation factor; Amino acids; AMPA receptors; Animals; Autism; Autistic Disorder - drug therapy; Autistic Disorder - genetics; Autistic Disorder - metabolism; Binding; Cytoskeleton; Domains; Genes; Guanine; Guanine nucleotide exchange factor; Guanine Nucleotide Exchange Factors - analysis; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Homology; Humans; Intellectual disabilities; intellectual disability; Intellectual Disability - drug therapy; Intellectual Disability - genetics; Intellectual Disability - metabolism; Kinases; Membrane trafficking; Molecular Targeted Therapy; Mutants; Mutation; Mutation - drug effects; Neurons; NMDA receptors; Nucleotides; Phosphoinositides; Pleckstrin; Proline; Protein Interaction Maps - drug effects; Proteins; Review; Self-assembly; Signal transduction; Signal Transduction - drug effects; Structure-function relationships; synaptic plasticity; AMPA receptors; synaptic plasticity; guanine nucleotide exchange factor; NMDA receptors; autism; intellectual disability
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20123038

Mutations in
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
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.