Mutations in the DLG3 Gene Cause Nonsyndromic X-Linked Mental Retardation

Abstract

We have identified truncating mutations in the human DLG3 (neuroendocrine dlg) gene in 4 of 329 families with moderate to severe X-linked mental retardation. DLG3 encodes synapse-associated protein 102 (SAP102), a member of the membrane-associated guanylate kinase protein family. Neuronal SAP102 is expressed during early brain development and is localized to the postsynaptic density of excitatory synapses. It is composed of three amino-terminal PDZ domains, an src homology domain, and a carboxyl-terminal guanylate kinase domain. The PDZ domains interact directly with the NR2 subunits of the NMDA glutamate receptor and with other proteins responsible for NMDA receptor localization, immobilization, and signaling. The mutations identified in this study all introduce premature stop codons within or before the third PDZ domain, and it is likely that this impairs the ability of SAP102 to interact with the NMDA receptor and/or other proteins involved in downstream NMDA receptor signaling pathways. NMDA receptors have been implicated in the induction of certain forms of synaptic plasticity, such as long-term potentiation and long-term depression, and these changes in synaptic efficacy have been proposed as neural mechanisms underlying memory and learning. The disruption of NMDA receptor targeting or signaling, as a result of the loss of SAP102, may lead to altered synaptic plasticity and may explain the intellectual impairment observed in individuals with DLG3 mutations.

Fragile X Mental Retardation Protein Regulates the Levels of Scaffold Proteins and Glutamate Receptors in Postsynaptic Densities

“…In both the neocortex and the hippocampus, postsynaptic levels of two scaffold proteins related to SAP97, namely PSD-95 and SAP102, were found to be identical in wild-type and FMRPdeficient mice. Despite the fact that PSD-95-and SAP102-deficient mice exhibit impaired learning (64,65) and functional loss of SAP102 results in mental retardation in humans (66), our data suggest that both proteins do not significantly contribute to the learning disabilities of FXS patients. Interestingly, we and others have identified PSD-95 mRNA as an in vivo FMRP target (21,22,36,67).…”

CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes

“…13,14 cDNA preparation and RT-PCR Reverse transcriptase PCR (RT-PCR) was carried out using standard techniques as previously described. 15,16 …”

Genetics and pathophysiology of mental retardation

“…Mutations identified in DLG3 shown to be associated with MR are predicted to impair the ability of SAP102 to interact with NMDA receptors and/or other proteins involved in downstream NMDA receptor signaling pathways. 50 For the two other XLMR-related genes, GDI1 52,53 and IL1RAPL, 51 literature data are also suggesting their participation in the regulation of synaptic activity. In the mammalian brain, GDIa encoded by the GDI1 gene is the most abundant form of GDI in the CNS and was thought to be involved in the regulation of Rab proteins, which participate in synaptic vesicle recycling and fusion.…”