SYN2 is an autism predisposing gene: loss-of-function mutations alter synaptic vesicle cycling and axon outgrowth.
SYN2 is an autism predisposing gene: loss-of-function mutations alter synaptic vesicle cycling and axon outgrowth.
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DOI：
10.1093/hmg/ddt401
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发表时间：
2014-01-01
影响因子：
3.5
通讯作者：
Cossette P
中科院分区：
文献类型：
--
作者：
Corradi A;Fadda M;Piton A;Patry L;Marte A;Rossi P;Cadieux-Dion M;Gauthier J;Lapointe L;Mottron L;Valtorta F;Rouleau GA;Fassio A;Benfenati F;Cossette P
越来越多的基因诱发自闭症谱系障碍（ASD）已被确定，其中许多涉及突触功能。这种“突触自闭症通路”特别包括SYN 1的破坏，SYN 1与人类和小鼠模型中的癫痫，自闭症和异常行为有关。突触蛋白是一个多基因家族的神经元特异性磷蛋白（SYN 1 -3），存在于大多数突触中，参与调节神经递质的释放和突触发生。突触蛋白I和II是成年大脑中主要的Syn亚型，显示出部分重叠的功能，并且两种亚型的缺陷与小鼠的癫痫和自闭症样行为相关。在这项研究中，我们发现SYN 2中的无义（A94 fs 199 X）和错义（Y236 S和G464 R）突变与人类ASD相关。该表型在雄性中很明显。SYN 2突变的女性携带者不受影响，这表明SYN 2是ASD中常染色体性别限制表达的另一个例子。当在SYN 2敲除神经元中表达时，野生型人Syn II完全挽救SYN 2敲除表型，而无义突变体不表达并且错义突变体实际上不能修饰SYN 2敲除表型。 这些结果首次确定SYN 2作为ASD的一种新的易感基因，并加强了ASD的突触稳态紊乱的假设。
An increasing number of genes predisposing to autism spectrum disorders (ASDs) has been identified, many of which are implicated in synaptic function. This ‘synaptic autism pathway’ notably includes disruption of SYN1 that is associated with epilepsy, autism and abnormal behavior in both human and mice models. Synapsins constitute a multigene family of neuron-specific phosphoproteins (SYN1-3) present in the majority of synapses where they are implicated in the regulation of neurotransmitter release and synaptogenesis. Synapsins I and II, the major Syn isoforms in the adult brain, display partially overlapping functions and defects in both isoforms are associated with epilepsy and autistic-like behavior in mice. In this study, we show that nonsense (A94fs199X) and missense (Y236S and G464R) mutations in SYN2 are associated with ASD in humans. The phenotype is apparent in males. Female carriers of SYN2 mutations are unaffected, suggesting that SYN2 is another example of autosomal sex-limited expression in ASD. When expressed in SYN2 knockout neurons, wild-type human Syn II fully rescues the SYN2 knockout phenotype, whereas the nonsense mutant is not expressed and the missense mutants are virtually unable to modify the SYN2 knockout phenotype. These results identify for the first time SYN2 as a novel predisposing gene for ASD and strengthen the hypothesis that a disturbance of synaptic homeostasis underlies ASD.
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影响因子：
30.8
作者：
Durand, Christelle M.;Betancur, Catalina;Bourgeron, Thomas
通讯作者：
Bourgeron, Thomas
DOI：
10.1007/s11068-008-9030-y
发表时间：
2008-08-01
期刊：
BRAIN CELL BIOLOGY
影响因子：
--
作者：
Fernandez-Alfonso, Tomas;Ryan, Timothy A.
通讯作者：
Ryan, Timothy A.
影响因子：
6.9
作者：
BAILEY, A;LECOUTEUR, A;RUTTER, M
通讯作者：
RUTTER, M
影响因子：
48
作者：
Cavalleri, Gianpiero L.;Weale, Michael E.;Goldstein, David B.
通讯作者：
Goldstein, David B.
影响因子：
2.2
作者：
Etholm, Lars;Bahonjic, Elma;Heggelund, Paul
通讯作者：
Heggelund, Paul