Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation
Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation
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DOI：
10.1086/422703
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发表时间：
2004-08-01
影响因子：
9.8
通讯作者：
Raymond, FL
中科院分区：
文献类型：
--
作者：
Tarpey, P;Parnau, J;Raymond, FL
我们在 329 个中度至重度 X 连锁智力低下家庭中的 4 个家庭中发现了人类 DLG3（神经内分泌 dlg）基因的截短突变。 DLG3 编码突触相关蛋白 102 (SAP102)，它是膜相关鸟苷酸激酶蛋白家族的成员。神经元 SAP102 在早期大脑发育过程中表达，并定位于兴奋性突触的突触后密度。它由三个氨基端 PDZ 结构域、一个 src 同源结构域和一个羧基端鸟苷酸激酶结构域组成。 PDZ 结构域直接与 NMDA 谷氨酸受体的 NR2 亚基以及负责 NMDA 受体定位、固定和信号传导的其他蛋白质相互作用。本研究中发现的突变均在第三个 PDZ 结构域内或之前引入过早终止密码子，这可能会损害 SAP102 与 NMDA 受体和/或参与下游 NMDA 受体信号传导途径的其他蛋白质相互作用的能力。 NMDA 受体与某些形式的突触可塑性的诱导有关，例如长期增强和长期抑制，并且这些突触功效的变化已被认为是记忆和学习的神经机制。 SAP102 缺失导致 NMDA 受体靶向或信号传导中断，可能会导致突触可塑性改变，并可能解释在具有 DLG3 突变的个体中观察到的智力障碍。
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.