Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation.
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.
Tarpey
Patrick
P
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom.
Parnau
Josep
J
Blow
Matthew
M
Woffendin
Hayley
H
Bignell
Graham
G
Cox
Charles
C
Cox
James
J
Davies
Helen
H
Edkins
Sarah
S
Holden
Simon
S
Korny
Angelique
A
Mallya
Uma
U
Moon
Jenny
J
O'Meara
Sarah
S
Parker
Adrian
A
Stephens
Philip
P
Stevens
Claire
C
Teague
Jon
J
Donnelly
Andrew
A
Mangelsdorf
Marie
M
Mulley
John
J
Partington
Michael
M
Turner
Gillian
G
Stevenson
Roger
R
Schwartz
Charles
C
Young
Ian
I
Easton
Douglas
D
Bobrow
Martin
M
Futreal
P Andrew
PA
Stratton
Michael R
MR
Gecz
Jozef
J
Wooster
Richard
R
Raymond
F Lucy
FL
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*
C116869:DLG3 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors