Fig. 1
From: The genetic basis of non-syndromic intellectual disability: a review
a The Nucleus: Many ID genes are involved in transcriptional regulation. Several of these genes encode transcription factors, such as the zinc fingers, PQBP1, ARX and FMR2. CC2D1A and TRAPPC9 activate the NF-κB transcription factor. Epigenetic regulation can also be seen in NS-ID genes. Mutations in genes encoding methyl-binding proteins like MeCP2, ATRX and MBD5, as well as chromatin remodeling proteins like JARID1C and BRWD3, result in ID. b The Glutamate Excitatory Synapse: The pre-synaptic portion of the excitatory synapse is where synaptic vesicles containing the neurotransmitter glutamate are exocytosed. The NS-ID-associated scaffolding protein CASK functions here, as do various other proteins involved in neurotransmitter release that have been implicated in NS-ID or autism, such as SNAP25, STXBP1, SYP, GDI1 and NRXN1. Postsynaptic excitatory synapses contain up to three types of ionotropic glutamate receptors as well as metabotropic glutamate receptors. In these receptors and their complex protein interactions, we find many proteins that are involved in NS-ID. Mutations in genes coding for subunits of ionotropic glutamate receptors, such as GLuR6 (Kainate receptor subunit) and GRIA3 (AMPAR subunit), cause MR. Additionally, many proteins in the postsynaptic density (PSD) including scaffolding and adhesion proteins (SAP102, SHANK3, NLGN4) have also been implied in the genetics of NS-ID and autism. CRBN is involved in regulating the expression of Ca2+ dependant K+ channels (BKCa, encoded by KCNMA1), and resulting ionic currents, at the synapse. IL1RAPL1, a relatively common genetic cause of NS-MR and autism is present in the PSD, as are OPHN1 and SYNGAP, which is a cause of autosomal dominant NS-ID. SYNGAP activates RAS, which leads to several signal transduction pathways resulting in transcriptional activation, including the ERK/MAP and RHO pathways, each of which have downstream effectors that are coded for other NS-ID related genes (Rho: PAK3, OPHN1, ARHGEF6, FGD1, DOCK8; ERK/MAPK: RPS6KA3, PAK3). A number of other autism or ID-associated proteins are also believed to function at the synapse (DPP6, DPP10, PCDH9, SLC6A8, PRSS12), but are not shown in this representation (Molinari et al. 2002; Hahn et al. 2002; Marshall et al. 2008; Hynes et al. 2009)