Cited by 176Genetics and Neurodevelopmental DisordersDown syndrome and intellectual disability researchNeuroscience and Neuropharmacology Research

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

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Tarpey, Patrick, Parnau, Josep, Blow, Matthew, Woffendin, Hayley, Bignell, Graham, Cox, Charles, Cox, James, Davies, Helen +25 more·2004·The American Journal of Human Genetics

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.

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Authors
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.
Affiliations
  • Wellcome Sanger Institute (GB)
  • University of Cambridge (GB)
  • Women's and Children's Hospital (AU)
  • Hunter Genetics (AU)
  • Greenwood Genetic Center (US)
  • Leicester Royal Infirmary (GB)
Corresponding author
Raymond, F. Lucy
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2004-08
Volume
75
Issue
2
Pages
318-324
ISSN
0002-9297 (ISSN-L)
OpenAlex
W2033793228
Cited by
176
References
29
Citations by year
2026: 3 · 2025: 4 · 2024: 6 · 2023: 3 · 2022: 2 · 2021: 11 · 2020: 8 · 2019: 9 · 2018: 8 · 2017: 9 · 2016: 6 · 2015: 9 · 2014: 9 · 2013: 8 · 2012: 13
FWCI
4.46
Type
journal article
Language
en
Open access
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Wellcome Trust
  • National Institutes of Health (5r01hd026202-15)
  • National Institute of Child Health and Human Development
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01-HD026202, HD 26202)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
DLG3, SAP102, X-linked intellectual disability, truncating mutations, PDZ domain, NMDA receptor, postsynaptic density, synaptic plasticity, long-term potentiation, long-term depression, membrane-associated guanylate kinase
MeSH terms
Base Sequence, Female, Humans, Male, Molecular Sequence Data, Nuclear Proteins, Pedigree, Transcription Factors, Sequence Deletion, Mental Retardation, X-Linked, X-Linked Intellectual Disability, Chromosomes, Human, X

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