title: 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.
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tarpey
authors.forename: Josep
authors.initials: J
authors.lastname: Parnau
authors.forename: Matthew
authors.initials: M
authors.lastname: Blow
authors.forename: Hayley
authors.initials: H
authors.lastname: Woffendin
authors.forename: Graham
authors.initials: G
authors.lastname: Bignell
authors.forename: Charles
authors.initials: C
authors.lastname: Cox
authors.forename: James
authors.initials: J
authors.lastname: Cox
authors.forename: Helen
authors.initials: H
authors.lastname: Davies
authors.forename: Sarah
authors.initials: S
authors.lastname: Edkins
authors.forename: Simon
authors.initials: S
authors.lastname: Holden
authors.forename: Angelique
authors.initials: A
authors.lastname: Korny
authors.forename: Uma
authors.initials: U
authors.lastname: Mallya
authors.forename: Jenny
authors.initials: J
authors.lastname: Moon
authors.forename: Sarah
authors.initials: S
authors.lastname: O'Meara
authors.forename: Adrian
authors.initials: A
authors.lastname: Parker
authors.forename: Philip
authors.initials: P
authors.lastname: Stephens
authors.forename: Claire
authors.initials: C
authors.lastname: Stevens
authors.forename: Jon
authors.initials: J
authors.lastname: Teague
authors.forename: Andrew
authors.initials: A
authors.lastname: Donnelly
authors.forename: Marie
authors.initials: M
authors.lastname: Mangelsdorf
authors.forename: John
authors.initials: J
authors.lastname: Mulley
authors.forename: Michael
authors.initials: M
authors.lastname: Partington
authors.forename: Gillian
authors.initials: G
authors.lastname: Turner
authors.forename: Roger
authors.initials: R
authors.lastname: Stevenson
authors.forename: Charles
authors.initials: C
authors.lastname: Schwartz
authors.forename: Ian
authors.initials: I
authors.lastname: Young
authors.forename: Douglas
authors.initials: D
authors.lastname: Easton
authors.forename: Martin
authors.initials: M
authors.lastname: Bobrow
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.forename: Richard
authors.initials: R
authors.lastname: Wooster
authors.forename: F Lucy
authors.initials: FL
authors.lastname: Raymond
mesh_terms: D001483:Base Sequence; D041321:Chromosomes, Human, X; D005260:Female; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C116869:DLG3 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors