Disease relevance of DLG3

• Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation [1].
• NE-Dlg also directly interacts with the colorectal tumor suppressor adenomatous polyposis coli, suggesting that it may play a role in regulating cell proliferation in epithelial cells [2].
• RSK2 is involved in Coffin-Lowry syndrome and nonspecific MRX [3].
• Large deletions in Xq21 often are associated with contiguous gene syndromes consisting of X-linked deafness type 3 (DFN3), mental retardation (MRX), and choroideremia (CHM) [3].
• At the present time, there is increasing evidence that the FG syndrome-phenotype may be present in different XLMR conditions, e.g. the fragile X syndrome [4].

Psychiatry related information on DLG3

• Abnormal expression of SAP-102 in schizophrenia and SAP-102 and PSD-95 in mood disorders in subcortical structures receiving afferent glutamatergic innervation from frontal cortex suggests dysregulation of cortical-subcortical circuitry in these illnesses [5].
• Results: There was a significant decrease in the expression of transcripts for NR1 and NR2A subunits and SAP102 in bipolar disorder [6].
• Indeed, over the past 2 years significant progress has been made in understanding the molecular basis underlying not only XLMR, where there are distinguishing phenotypic or genetic markers (syndromal forms of XLMR), but also non-specific (or idiopathic) mental retardation (MRX) [7].

High impact information on DLG3

• Thorough investigation of an MRX critical region in Xp22.1-21.3 enabled us to identify a new gene expressed in brain that is responsible for a non-specific form of X-linked mental retardation [8].
• We review the potential roles in brain plasticity of two membrane-associated guanylate kinases (MAGUKs), SAP102 and PSD95, which form a scaffold for the ion-passing glutamate receptors at the postsynaptic density, and we consider the known functional significance of these molecules in subunit switching [9].
• At immature synapses, PSD-95 and PSD-93 play little role in synaptic AMPA-R clustering; instead, SAP-102 dominates [10].
• Analysis of linkage intervals from 125 unrelated families with nonsyndromic X-linked mental retardation (NS-XLMR) has revealed that the respective gene defects are conspicuously clustered in defined regions of the human X-chromosome, with approximately 30% of all mutations being located on the proximal Xp [11].
• In a systematic screen of brain-expressed genes from this region in 210 families with XLMR, we identified seven different mutations in JARID1C, including one frameshift mutation and two nonsense mutations that introduce premature stop codons, as well as four missense mutations that alter evolutionarily conserved amino acids [12].

Biological context of DLG3

• Using human-hamster radiation hybrid mapping panels, we mapped DLG3 to Xq13.1 and established a sequence-tagged site marker map of the surrounding region [2].
• To explore the genetic control of NE-Dlg, we developed a physical map of the chromosome region containing DLG3, the locus encoding NE-Dlg [2].
• We show that Pyk2 effectively binds to the Src homology 3 (SH3) domain of SAP102 only when the GK domain is removed from the SH3 domain [13].
• Two unrelated mildly retarded males with inversions of the X chromosome and non-specific mental retardation (MRX) are described [14].
• We report on deletion mapping and X inactivation analysis of a gene for X linked non-specific mental retardation (MRX) at Xp21.3-Xp22.11, on the basis of molecular studies in two families with Xp microdeletions involving the DAX-1 gene [15].

Anatomical context of DLG3

• SAP102 levels were also significantly reduced in the hippocampus of schizophrenic patients, but this reduction was correlated with sample storage time and post-mortem interval [16].
• NE-dlg/SAP102, a neuronal and endocrine tissue-specific MAGUK family protein, was found to be expressed in both dendrites and cell bodies in neuronal cells [17].
• MRX analyzed 129 of the 130 available vertebrae in group 1 at both visits and 141 of the 143 available in group 2, while MXA analyzed 124 vertebrae in group 1 at both visits and 127 in group 2 [18].
• Restudy of the original marker-X family confirmed recent observations that this XLMR disorder is associated with large testes and slightly abnormal ears [19].
• At the 1983 NIH workshop on XLMR there was a general consensus that a connective tissue dysplasia is a component of the Martin-Bell syndrome, a fact since confirmed by others on the basis of objective measurements of finger joint hypermobility and frequent presence of mitral valve prolapse [20].

Physical interactions of DLG3

• 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 [1].
• NE-dlg/SAP102 is shown to interact with only the S form of nedasin which is predominantly expressed in brain [17].

Co-localisations of DLG3

• The expression of nedasin in neuronal cells increases in parallel with the progress of synaptogenesis and is mainly detected in cell bodies where it co-localizes with NE-dlg/SAP102 [17].

Other interactions of DLG3

• We detected these proteins, apart from SAP102, in parathyroid chief cells, a cell type having a marked expression of megalin [21].
• Neuroendocrine-Dlg (NE-Dlg) is a member of the discs-large-related (DLG) subfamily of the membrane-associated guanylate kinase-related protein family [2].
• 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 [1].
• Here we report the isolation of a novel NE-dlg/SAP102-associated protein, p51-nedasin [17].
• Decreased NR1, NR2A, and SAP102 transcript expression in the hippocampus in bipolar disorder [6].

Analytical, diagnostic and therapeutic context of DLG3

• Using a surface plasmon resonance measurement system, we detected specific binding of recombinant NE-dlg/SAP102 to the immobilized calmodulin with a Kd value of 44 nM [22].
• Although conventionally it has been performed on lateral radiographs of the thoracolumbar spine (morphometric radiography, MRX), it may now be accomplished on morphometric X-ray absorptiometry (MXA) scans, acquired on dual-energy X-ray absorptiometry (DXA) machines [18].

References