Disorder-associated mutations lead to functional inactivation of neuroligins
Disorder-associated mutations lead to functional inactivation of neuroligins
复制标题
DOI：
10.1093/hmg/ddh158
复制
发表时间：
2004-07-15
影响因子：
3.5
通讯作者：
Scheiffele, P
中科院分区：
文献类型：
--
作者：
Chih, B;Afridi, SK;Scheiffele, P
自闭症是一种神经发育综合征，影响0.1-0.5%的人口。已经提出，神经元回路和/或神经元信号传导的改变是导致自闭症患者行为和认知畸变的原因。然而，这种改变的细胞基础是未知的。最近，神经细胞粘附分子家族中的点突变被认为与自闭症谱系障碍和精神发育迟滞有关。我们研究了这些疾病相关突变对神经连接素功能的影响。我们证明，点突变精氨酸451和无义突变天冬氨酸396的神经连接素-3和-4（NL 3和NL 4），分别导致细胞内滞留的突变蛋白。野生型NL 3和NL 4蛋白在海马神经元中的过表达刺激突触前末梢的形成，而疾病相关突变导致这种突触功能的丧失。我们的研究结果表明，先前确定的神经连接素基因突变可能与自闭症谱系障碍和精神发育迟滞的神经发育缺陷有关，因为它们损害了突触细胞粘附分子的功能。
Autism is a neuro-developmental syndrome that affects 0.1-0.5% of the population. It has been proposed that alterations in neuronal circuitry and/or neuronal signaling are responsible for the behavioral and cognitive aberrations in autism patients. However, the cellular basis of such alterations is unknown. Recently, point mutations in a family of neuronal cell adhesion molecules called neuroligins have been linked to autism-spectrum disorders and mental retardation. We investigated the consequences of these disease-associated mutations on neuroligin function. We demonstrate that the point mutation at arginine 451 and a nonsense mutation at aspartate 396 of neuroligin-3 and -4 (NL3 and NL4), respectively, result in intracellular retention of the mutant proteins. Over-expression of wild-type NL3 and NL4 proteins in hippocampal neurons stimulates the formation of presynaptic terminals, whereas the disease-associated mutations result in a loss of this synaptic function. Our findings suggest that the previously identified mutations in neuroligin genes are likely to be relevant for the neuro-developmental defects in autism-spectrum disorders and mental retardation since they impair the function of a synaptic cell adhesion molecule.