Alternative titles; symbols
HGNC Approved Gene Symbol: DLG4
Cytogenetic location: 17p13.1 Genomic coordinates (GRCh38): 17:7,187,187-7,220,050 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.1 | Intellectual developmental disorder, autosomal dominant 62 | 618793 | Autosomal dominant | 3 |
DLG4 belongs to the discs large (DLG) subfamily of the membrane-associated guanylate kinase (MAGUK) family (see DLG1; 601014). DLG4 interacts with both N-methyl-D-aspartate (NMDA) receptors (see 138249) and Shaker-type potassium channels (see 176260) and plays an important role in the formation and maintenance of synaptic junctions (Zhou and Blumberg, 2003).
Proteins related to Drosophila 'discs large' (Dlg) are associated with the cortical actin cytoskeleton and appear to have both structural and functional roles. By screening a human mammary gland cDNA library with a human EST showing homology to rat Psd95, which is also known as Sap90 (Kistner et al., 1993), Stathakis et al. (1997) cloned a cDNA encoding DLG4, which they called PSD95. The predicted 723-amino acid DLG4 protein has 3 PSD95-DLG-Z01 (PDZ) domains in its N-terminal half, a central src homology-3 (SH3) motif, and a C-terminal guanylate kinase (GUK)-homologous domain. The human DLG4 protein is 99% identical to the rat and mouse Psd95 proteins and 56% identical to the Drosophila Dlg protein. Northern blot analysis detected 6 DLG4 transcripts with different expression patterns, including a 4.2-kb transcript that was variably expressed in all 17 human tissues examined. Western blot analysis using antibodies against DLG4 detected multiple proteins with complex distribution patterns, including a ubiquitous 85-kD and tissue-specific variants.
By examining human brain, mammary gland, pancreas, and testis cDNA libraries, Stathakis et al. (1999) identified 3 splice variants of DLG4. A transcript lacking exon 3 was detected in brain, but not in other tissues. This variant introduces an early frameshift and encodes a predicted 45-amino acid peptide. However, a downstream ORF from exons 4 through 22 has the potential to encode a 664-amino acid protein containing all functional domains of DLG4, with a single residue before the first PDZ domain. A variant lacking exon 20 was detected in mammary gland and testis, but not in brain or pancreas. This variant encodes a deduced 670-amino acid protein that lacks part of the C-terminal GUK domain. A variant containing a 99-nucleotide extension of exon 4 (exon 4b) was detected in testis, but not in other tissues. This variant encodes a deduced 803-amino acid protein with 33 additional amino acids inserted before the first PDZ domain.
Zhou and Blumberg (2003) stated that the N terminus of DLG4 is modified by thioester-linked palmitate, which targets the protein to cell membranes. Palmitoylation is also a critical regulatory mechanism for receptor interactions with DLG4. Real-time RT-PCR detected DLG4 expression in all tissues examined, with highest expression in brain, followed by heart, placenta, lung, pancreas, spleen, thymus, testis, ovary, and small intestine.
The proper distribution of voltage-gated and ligand-gated ion channels on the neuronal surface is critical for the processing and transmission of electrical signals in neurons. Kim et al. (1995) and Kim et al. (1996) demonstrated that PSD95 and chapsyn-110 (603583) mediated clustering of both NMDA receptors and potassium channels. Chapsyn-110 and PSD95 heteromultimerized with each other and were recruited into the same NMDA receptor and potassium channel clusters. Kim et al. (1996) suggested that these 2 proteins may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins.
In cultured cortical neurons, Sattler et al. (1999) suppressed expression of the NMDA receptor scaffolding protein PSD95 and observed selective attenuation of excitotoxicity triggered via NMDA receptors, but not by other glutamate or calcium ion channels. NMDA receptor function was unaffected because receptor expression, NMDA currents, and calcium-45 loading were unchanged. Suppressing PSD95 blocked calcium-activated nitric oxide production by NMDA receptors selectively without affecting neuronal nitric oxide synthase expression or function. Thus, PSD95 is required for efficient coupling of NMDAR activity to nitric oxide toxicity and imparts specificity to excitotoxic calcium signaling.
El-Husseini et al. (2000) found that overexpression of PSD95 in hippocampal neurons could drive maturation of glutamatergic synapses. PSD95 expression enhanced postsynaptic clustering and activity of glutamate receptors. Postsynaptic expression of PSD95 also enhanced maturation of the presynaptic terminal. These effects required synaptic clustering of PSD95 but did not rely on its guanylate kinase domain. PSD95 expression also increased the number and size of dendritic spines. El-Husseini et al. (2000) concluded that PSD95 can orchestrate synaptic development and suggested that PSD95 has a role in synapse stabilization and plasticity.
Neuregulins and their receptors, the ERBB protein tyrosine kinases, are essential for neuronal development, but their functions in the adult central nervous system are unknown. Huang et al. (2000) reported that ERBB4 (600543) is enriched in the postsynaptic density and associates with PSD95. Heterologous expression of PSD95 enhanced NRG (142445) activation of ERBB4 and MAP kinase (see 176948). Conversely, inhibiting expression of PSD95 in neurons attenuated NRG-mediated activation of MAP kinase. PSD95 formed a ternary complex with 2 molecules of ERBB4, suggesting that PSD95 facilitates ERBB4 dimerization. Finally, NRG suppressed induction of long-term potentiation in the hippocampal CA1 region without affecting basal synaptic transmission. Thus, NRG signaling may be synaptic and regulated by PSD95. Huang et al. (2000) concluded that a role of NRG signaling in the adult central nervous system may be modulation of synaptic plasticity.
Garcia et al. (2000) found that Erbb4 and Psd95 coimmunoprecipitated from rat forebrain lysates and that the direct interaction was mediated through the C-terminal end of Erbb4. Immunofluorescent studies of cultured rat hippocampal cells showed that Erbb4 colocalized with Psd95 and NMDA receptors at interneuronal postsynaptic sites. The findings suggested that certain ERBB receptors interact with other receptors and may be important in activity-dependent synaptic plasticity.
El-Husseini et al. (2002) identified palmitate cycling on PSD95 at the synapse and found that palmitate turnover on PSD95 is regulated by glutamate receptor activity. Acutely blocking palmitoylation dispersed synaptic clusters of PSD95 and caused a selective loss of synaptic AMPA receptors (e.g., GRIA1; 138248). The authors also found that rapid glutamate-mediated AMPA receptor internalization requires depalmitoylation of PSD95. In a nonneuronal model system, clustering of PSD95, stargazin (602911), and AMPA receptors was also regulated by ongoing palmitoylation of PSD95 at the plasma membrane. El-Husseini et al. (2002) concluded that palmitate cycling on PSD95 can regulate synaptic strength and activity-dependent plasticity.
To treat stroke without blocking NMDA receptors, Aarts et al. (2002) transduced neurons with peptides that disrupted the interaction of NMDA receptors with the postsynaptic density protein PSD95. This procedure dissociated NMDA receptors from downstream neurotoxic signaling without blocking synaptic activity or calcium influx. The peptides, when applied either before or 1 hour after an insult, protected cultured neurons from excitotoxicity, reduced focal ischemic brain damage in rats, and improved their neurologic function. Aarts et al. (2002) concluded that their approach circumvents the negative consequences associated with blocking NMDA receptors and may constitute a practical stroke therapy.
In cotransfection experiments, Tanemoto et al. (2002) showed that Kir5.1 (KCNJ16; 605722) assembled to form a functional homomeric potassium channel by interacting with PSD95. The authors observed that Kir5.1 expressed alone was distributed mostly in the cytoplasm, but Kir5.1 coexpressed with PSD95 was located on the plasma membrane in a clustered manner. Using GST pull-down studies, Tanemoto et al. (2002) identified domains responsible for Kir5.1/PSD95 interaction. They reported that protein kinase A (PKA)-mediated phosphorylation of Kir5.1 disrupted the binding of Kir5.1 with PSD95. Tanemoto et al. (2002) hypothesized that Kir5.1/PSD95 forms a functional brain potassium channel that may be a physiologic target of PKA-mediated signaling. They concluded that PSD95 mediates formation of a functional potassium channel in the brain.
Conroy et al. (2003) showed that PDZ-containing proteins of the Psd95 family were required for maturation of functional nicotinic synapses in embryonic chicken ciliary ganglia. These proteins also helped mediate downstream activation of transcription factors.
Colledge et al. (2003) found that Psd95 interacted with and was ubiquitinated by the E3 ligase Mdm2 (164785). In response to NMDA receptor activation in cultured rat hippocampal neurons, Psd95 was ubiquitinated and rapidly removed from synaptic sites by proteasome-dependent degradation. Mutations that blocked Psd95 ubiquitination prevented NMDA-induced AMPA receptor endocytosis. Likewise, proteasome inhibitors prevented NMDA-induced AMPA receptor internalization and synaptically induced long-term depression. Colledge et al. (2003) concluded that ubiquitination of PSD95 through an MDM2-mediated pathway regulates AMPA receptor surface expression during synaptic plasticity.
Bao et al. (2004) found that sound-induced synaptic activity in the mouse cochlea increased the level of nuclear neuregulin-1 intracellular domain (Nrg-ICD) and upregulated PSD95 in postsynaptic spiral ganglion neurons. Nrg-ICD enhanced the transcriptional activity of the PSD95 promoter by binding to Eos (606239), a zinc finger transcription factor. The findings identified a molecular basis for activity-dependent synaptic plasticity.
By yeast 2-hybrid analysis of a mouse brain cDNA library, Li et al. (2006) found that Gng13 (607298) interacted with Psd95. Mutation analysis showed that the interaction involved the third PDZ domain of Psd95 and the C-terminal CAAX motif of Gng13. Coexpression of Gng13 with its G protein partner, Gnb1 (139380), did not interfere with the interaction. Coimmunoprecipitation analysis confirmed the interaction between Psd95 and Gng13.
Aartsen et al. (2006) found that Mpp4 -/- mouse retinas showed downregulation of Psd95 and mislocalization of both Psd95 and Veli3 (LIN7C; 612332) at the photoreceptor presynaptic membrane. They proposed that MPP4 may function as a recruitment factor to organize signal transducers at the photoreceptor synapse.
Kim et al. (2007) showed that phosphorylation of Psd95 in rat hippocampal neurons enhanced Psd95 synaptic accumulation and the ability of Psd95 to recruit surface AMPA receptors and potentiate excitatory postsynaptic currents. They determined that the Rac1 (602048)-Jnk1 (MAPK8; 601158) signaling pathway mediated this phosphorylation. Overexpression of a phosphomimicking mutant of Psd95 inhibited NMDA-induced AMPA receptor internalization and blocked induction of long-term depression.
Using PSD95 inhibitors, which uncouple postsynaptic density protein PSD95 from neurotoxic signaling pathways, in gyrencephalic nonhuman primates (cynomolgus macaques), Cook et al. (2012) showed that stroke damage can be prevented when a PSD95 inhibitor is administered after stroke onset in clinically relevant situations. The treatment reduced infarct volumes as gauged by MRI and histology, preserved the capacity of ischemic cells to maintain gene transcription in genomewide screens of ischemic brain tissue, and significantly preserved neurologic function in neurobehavioral assays. The degree of tissue neuroprotection by MRI corresponded strongly to the preservation of neurologic function, supporting the intuitive but unproven dictum that integrity of brain tissue can reflect functional outcome. Cook et al. (2012) concluded that their findings established that tissue neuroprotection and improved functional outcome after stroke is unequivocally achievable in gyrencephalic nonhuman primates treated with PSD95 inhibitors.
Stathakis et al. (1999) determined that the DLG4 gene contains 22 exons and spans about 30 kb. All splice sites conform to the GT-AG rule, except for the splice acceptor site of intron 5, which is TG instead of AG. The promoter region contains no TATA or CAAT boxes, but has a large GC-rich domain with characteristics of a CpG island.
Zhang et al. (2003) noted that the VLCAD (609575) and the DLG4 genes are located in a head-to-head orientation on chromosome 17p. The transcribed regions of the 2 genes overlap by about 220 bp. Using serial promoter partial deletion constructs in a reporter gene assay, they found that the essential promoter activity of DLG4 is carried within a region of about 400 bp and covers the entire VLCAD minimal promoter, which spans about 270 bp. The results from di-(2-ethylhexyl) phthalate (DEHP)-treated HepG2 cells revealed that the minimal VLCAD promoter can upregulate VLCAD expression in response to DEHP treatment. Site-directed mutagenesis experiments showed that a mutated AP2 (107580)-binding site markedly reduced the transcriptional activity of both the VLCAD and DLG4 promoters and abolished the minimal VLCAD promoter's response to DEHP treatment.
Independently, Zhou and Blumberg (2003) determined that the VLCAD and DLG4 genes overlap. The 2 genes share 245 nucleotides at their 5-prime ends, and the transcription start site for DLG4 extends into the coding region of VLCAD exon 1. The upstream regions of the VLCAD and DLG4 genes, including the overlapping region, contain 2 potential TATA-less promoters with potential binding sites for several common transcription factors. RT-PCR detected unique patterns of expression for VLCAD and DLG4, indicating that, although they share common regulatory elements, VLCAD and DLG4 also have distinct tissue-specific elements. The mouse Dlg4 and Vlcad genes are oriented in a head-to-head manner, but they do not overlap and are separated by almost 3.5 kb.
By radiation hybrid mapping, Stathakis et al. (1997) localized the DLG4 gene to chromosome 17p13.1.
In 3 unrelated patients with autosomal dominant intellectual developmental disorder-62 (MRD62; 618793), Lelieveld et al. (2016) identified 3 different de novo heterozygous frameshift or nonsense mutations in the DLG4 gene (602887.0001-602887.0003). The mutations, which were found by trio-based exome sequencing and confirmed by Sanger sequencing, were not found in the dbSNP (build 137) database. Functional studies of the variants and studies of patient cells were not performed, but all variants were predicted to result in haploinsufficiency. The patients were ascertained from a cohort of 820 individuals with intellectual disability who underwent trio-based exome sequencing.
In 3 unrelated adult males with MRD62, Moutton et al. (2018) identified heterozygous loss-of-function mutations in the DLG4 gene (602887.0004-602887.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in public databases, including gnomAD. The mutations occurred de novo in 2 patients; paternal DNA from the third patient was not available. Analysis of cells derived from 2 patients showed a 50% decrease in mRNA, suggesting that the mutation resulted in nonsense-mediated mRNA decay. Cells derived from the third patient, who had a splice site mutation, suggested production of an abnormal mRNA that would result in premature protein termination. The patients were ascertained from a cohort of 64 individuals with intellectual disability who also had some clinical marfanoid features.
Specific patterns of neuronal firing induce changes in synaptic strength that may contribute to learning and memory. If the postsynaptic NMDA receptors are blocked, long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission and the learning of spatial information are prevented. The NMDA receptor can bind PSD95, which may regulate the localization of and/or signaling by the receptor. Migaud et al. (1998) found that in mutant mice lacking Psd95, the frequency function of NMDA-dependent LTP and LTD was shifted to produce strikingly enhanced LTP at different frequencies of synaptic stimulation. In keeping with neural-network models that incorporate bidirectional learning rules, this frequency shift was accompanied by severely impaired spatial learning. Synaptic NMDA-receptor currents, subunit expression, localization, and synaptic morphology were all unaffected in the mutant mice. PSD95 thus appears to be important in coupling the NMDA receptor to pathways that control bidirectional synaptic plasticity and learning.
Using microarray analysis, Yao et al. (2004) identified Psd95 among a small number of genes whose expression was downregulated in Dat (SLC6A3; 126455) -/- mice, Net (SLC6A2; 163970) -/- mice, and Vmat2 (SLC18A2; 193001) +/- mice, all of which are models of dopamine supersensitivity, as well as in mice chronically treated with cocaine. In all 4 models, Psd95 mRNA and protein levels were downregulated in nucleus accumbens and caudate putamen. Psd95 protein was also decreased specifically in striatum, but not in cortex and hippocampus, of cocaine-treated animals. Enhanced long-term potentiation of frontocortico-accumbal glutamatergic synapses correlated with reduced Psd95 levels in all 4 models. Yao et al. (2004) also found that Psd95 -/- mice were supersensitive to cocaine and lacked chronic cocaine-induced behavioral plasticity.
Beique et al. (2006) found that Psd95-null mice had decreased glutamate AMPA receptor-mediated synaptic transmission but NMDA receptors were not affected. Although most of the affected synapses were located on morphologically mature dendritic spines, a significant population of synapses appeared unaffected by Psd95 depletion, suggesting that the functional role of Psd95 displays synapse specificity.
Feyder et al. (2010) found that Dlg4-null mice showed increased repetitive behaviors, abnormal communication and social behaviors, impaired motor coordination, and increased stress reactivity and anxiety-related responses compared to controls. Mutant mice also had subtle morphologic dendritic anomalies in the basolateral amygdala and altered forebrain expression of various synaptic genes. The phenotypic findings were reminiscent of autism spectrum disorders.
In a patient (patient 77) with autosomal dominant intellectual developmental disorder-62 (MRD62; 618793), Lelieveld et al. (2016) identified a de novo heterozygous 1-bp duplication (c.277dupA, NM_001365.3) in the DLG4 gene, predicted to result in a frameshift and premature termination (Y93fs). The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 137) database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in haploinsufficiency.
In a patient (patient 706) with autosomal dominant intellectual developmental disorder-62 (MRD62; 618793), Lelieveld et al. (2016) identified a de novo heterozygous c.1231C-T transition (c.1231C-T, NM_001365.3) in the DLG4 gene, resulting in an arg411-to-ter (R411X) substitution. The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 137) database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in haploinsufficiency.
In a patient (patient 747) with autosomal dominant intellectual developmental disorder-62 (MRD62; 618793), Lelieveld et al. (2016) identified a de novo heterozygous c.1054C-T transition (c.1054C-T, NM_001365.3) in the DLG4 gene, resulting in an arg352-to-ter (R352X) substitution. The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 137) database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in haploinsufficiency.
In a 23-year-old French man (patient 1) with autosomal dominant intellectual developmental disorder-62 (MRD62; 618793), Moutton et al. (2018) identified a de novo heterozygous 1-bp deletion (c.1843delG, NM_001365.3) in exon 19 of the DLG4 gene, resulting in a frameshift and premature termination (Glu615SerfsTer4). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in public databases, including gnomAD. Analysis of patient cells showed a 50% decrease in mRNA, suggesting that the mutation resulted in nonsense-mediated mRNA decay. The findings were consistent with haploinsufficiency.
In a 21-year-old man (patient 2) of French and Portuguese descent with autosomal dominant intellectual developmental disorder-62 (MRD62; 618793), Moutton et al. (2018) identified a de novo heterozygous 8-bp deletion (c.1147_1154del, NM_001365.3) in exon 11 of the DLG4 gene, resulting in a frameshift and premature termination (Phe383GlyfsTer31) in the PDZ3 domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in public databases, including gnomAD. Analysis of patient cells showed a 50% decrease in mRNA, suggesting that the mutation resulted in nonsense-mediated mRNA decay. The findings were consistent with haploinsufficiency.
In a 35-year-old man (patient 3) with autosomal dominant intellectual developmental disorder-62 (MRD62; 618793), Moutton et al. (2018) identified a heterozygous T-to-C transition (c.1672+2T-C, NM_001365.3) in intron 16 of the DLG4 gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in public databases, including gnomAD. The variant was not found in the mother; DNA from the father was unavailable. Analysis of patient cells showed that the mutation caused aberrant splicing predicted to result in a frameshift and premature termination (Gly558ProfsTer37). This change would cause disruption of the guanylate kinase domain.
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