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Gene Review

DLG3  -  discs, large homolog 3 (Drosophila)

Homo sapiens

Synonyms: Disks large homolog 3, KIAA1232, MRX, MRX90, NE-Dlg, ...
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Disease relevance of DLG3


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


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


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].


  1. Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation. Tarpey, P., Parnau, J., Blow, M., Woffendin, H., Bignell, G., Cox, C., Cox, J., Davies, H., Edkins, S., Holden, S., Korny, A., Mallya, U., Moon, J., O'Meara, S., Parker, A., Stephens, P., Stevens, C., Teague, J., Donnelly, A., Mangelsdorf, M., Mulley, J., Partington, M., Turner, G., Stevenson, R., Schwartz, C., Young, I., Easton, D., Bobrow, M., Futreal, P.A., Stratton, M.R., Gecz, J., Wooster, R., Raymond, F.L. Am. J. Hum. Genet. (2004) [Pubmed]
  2. DLG3, the gene encoding human neuroendocrine Dlg (NE-Dlg), is located within the 1.8-Mb dystonia-parkinsonism region at Xq13.1. Stathakis, D.G., Lee, D., Bryant, P.J. Genomics (1998) [Pubmed]
  3. A novel ribosomal S6-kinase (RSK4; RPS6KA6) is commonly deleted in patients with complex X-linked mental retardation. Yntema, H.G., van den Helm, B., Kissing, J., van Duijnhoven, G., Poppelaars, F., Chelly, J., Moraine, C., Fryns, J.P., Hamel, B.C., Heilbronner, H., Pander, H.J., Brunner, H.G., Ropers, H.H., Cremers, F.P., van Bokhoven, H. Genomics (1999) [Pubmed]
  4. Distinct facial appearance with nasal hypoplasia, constipation, severe mental retardation and hypotonia in two unrelated young males. Fryns, J.P., De Troch, C., Van Mol, C., Vandenbossche, L. Clin. Genet. (1996) [Pubmed]
  5. Abnormal striatal expression of transcripts encoding NMDA interacting PSD proteins in schizophrenia, bipolar disorder and major depression. Kristiansen, L.V., Meador-Woodruff, J.H. Schizophr. Res. (2005) [Pubmed]
  6. Decreased NR1, NR2A, and SAP102 transcript expression in the hippocampus in bipolar disorder. McCullumsmith, R.E., Kristiansen, L.V., Beneyto, M., Scarr, E., Dean, B., Meador-Woodruff, J.H. Brain Res. (2007) [Pubmed]
  7. Breakthroughs in molecular and cellular mechanisms underlying X-linked mental retardation. Chelly, J. Hum. Mol. Genet. (1999) [Pubmed]
  8. A new member of the IL-1 receptor family highly expressed in hippocampus and involved in X-linked mental retardation. Carrié, A., Jun, L., Bienvenu, T., Vinet, M.C., McDonell, N., Couvert, P., Zemni, R., Cardona, A., Van Buggenhout, G., Frints, S., Hamel, B., Moraine, C., Ropers, H.H., Strom, T., Howell, G.R., Whittaker, A., Ross, M.T., Kahn, A., Fryns, J.P., Beldjord, C., Marynen, P., Chelly, J. Nat. Genet. (1999) [Pubmed]
  9. Receptor compartmentalization and trafficking at glutamate synapses: a developmental proposal. van Zundert, B., Yoshii, A., Constantine-Paton, M. Trends Neurosci. (2004) [Pubmed]
  10. Synapse-Specific and Developmentally Regulated Targeting of AMPA Receptors by a Family of MAGUK Scaffolding Proteins. Elias, G.M., Funke, L., Stein, V., Grant, S.G., Bredt, D.S., Nicoll, R.A. Neuron (2006) [Pubmed]
  11. Nonsyndromic X-linked mental retardation: where are the missing mutations? Ropers, H.H., Hoeltzenbein, M., Kalscheuer, V., Yntema, H., Hamel, B., Fryns, J.P., Chelly, J., Partington, M., Gecz, J., Moraine, C. Trends Genet. (2003) [Pubmed]
  12. Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation. Jensen, L.R., Amende, M., Gurok, U., Moser, B., Gimmel, V., Tzschach, A., Janecke, A.R., Tariverdian, G., Chelly, J., Fryns, J.P., Van Esch, H., Kleefstra, T., Hamel, B., Moraine, C., Gecz, J., Turner, G., Reinhardt, R., Kalscheuer, V.M., Ropers, H.H., Lenzner, S. Am. J. Hum. Genet. (2005) [Pubmed]
  13. Interaction of the tyrosine kinase Pyk2 with the N-methyl-D-aspartate receptor complex via the Src homology 3 domains of PSD-95 and SAP102. Seabold, G.K., Burette, A., Lim, I.A., Weinberg, R.J., Hell, J.W. J. Biol. Chem. (2003) [Pubmed]
  14. Two unrelated patients with inversions of the X chromosome and non-specific mental retardation: physical and transcriptional mapping of their common breakpoint region in Xq13.1. Villard, L., Briault, S., Lossi, A.M., Paringaux, C., Belougne, J., Colleaux, L., Pincus, D.R., Woollatt, E., Lespinasse, J., Munnich, A., Moraine, C., Fontès, M., Gecz, J. J. Med. Genet. (1999) [Pubmed]
  15. Deletion mapping and X inactivation analysis of a non-specific mental retardation gene at Xp21.3-Xp22.11. Muroya, K., Kinoshita, E., Kamimaki, T., Matsuo, N., Yorifugi, T., Ogata, T. J. Med. Genet. (1999) [Pubmed]
  16. Selective reduction of a PDZ protein, SAP-97, in the prefrontal cortex of patients with chronic schizophrenia. Toyooka, K., Iritani, S., Makifuchi, T., Shirakawa, O., Kitamura, N., Maeda, K., Nakamura, R., Niizato, K., Watanabe, M., Kakita, A., Takahashi, H., Someya, T., Nawa, H. J. Neurochem. (2002) [Pubmed]
  17. A novel NE-dlg/SAP102-associated protein, p51-nedasin, related to the amidohydrolase superfamily, interferes with the association between NE-dlg/SAP102 and N-methyl-D-aspartate receptor. Kuwahara, H., Araki, N., Makino, K., Masuko, N., Honda, S., Kaibuchi, K., Fukunaga, K., Miyamoto, E., Ogawa, M., Saya, H. J. Biol. Chem. (1999) [Pubmed]
  18. Vertebral morphometry: a comparison of long-term precision of morphometric X-ray absorptiometry and morphometric radiography in normal and osteoporotic subjects. Rea, J.A., Chen, M.B., Li, J., Marsh, E., Fan, B., Blake, G.M., Steiger, P., Smith, I.G., Genant, H.K., Fogelman, I. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. (2001) [Pubmed]
  19. Restudy of the original marker X family. Lubs, H.A., Watson, M., Breg, R., Lujan, E. Am. J. Med. Genet. (1984) [Pubmed]
  20. Discovery of a connective tissue dysplasia in the Martin-Bell syndrome. Opitz, J.M., Westphal, J.M., Daniel, A. Am. J. Med. Genet. (1984) [Pubmed]
  21. Selective interaction of megalin with postsynaptic density-95 (PSD-95)-like membrane-associated guanylate kinase (MAGUK) proteins. Larsson, M., Hjälm, G., Sakwe, A.M., Engström, A., Höglund, A.S., Larsson, E., Robinson, R.C., Sundberg, C., Rask, L. Biochem. J. (2003) [Pubmed]
  22. Interaction of NE-dlg/SAP102, a neuronal and endocrine tissue-specific membrane-associated guanylate kinase protein, with calmodulin and PSD-95/SAP90. A possible regulatory role in molecular clustering at synaptic sites. Masuko, N., Makino, K., Kuwahara, H., Fukunaga, K., Sudo, T., Araki, N., Yamamoto, H., Yamada, Y., Miyamoto, E., Saya, H. J. Biol. Chem. (1999) [Pubmed]
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