SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice.
SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice.
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DOI：
10.1038/s41467-022-31566-z
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发表时间：
2022-07-15
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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作者：
SLITRK2 是一种在突触后神经元表达的单次跨膜蛋白，可调节神经突生长和兴奋性突触维持。在本研究中，我们报告了通过外显子组测序在患有神经发育障碍的个体中鉴定出的 X 染色体上 SLITRK2 的罕见变异（一种无义变异和六种错义变异）。功能研究表明，一些变体表现出膜运输受损和兴奋性突触促进作用受损。引人注目的是，这些变异消除了 SLITRK2 野生型降低神经元中受体酪氨酸激酶 TrkB 水平的能力。此外，Slitrk2条件性敲除小鼠表现出长期记忆受损和步态异常，重现了SLITRK2变异患者的部分临床特征。此外，Slitrk2 的海马 CA1 特异性 cKO 诱导的兴奋性突触维持受损导致空间参考记忆异常。总的来说，这些数据表明 SLITRK2 参与 X 连锁神经发育障碍，这些障碍是由 SLITRK2 功能的各个方面的扰动引起的。 SLITRK2 蛋白在突触通讯中发挥着重要作用。这项研究确定了 X 连锁 SLITRK2 变异，该变异通过损害兴奋性突触而导致神经发育障碍。
SLITRK2 is a single-pass transmembrane protein expressed at postsynaptic neurons that regulates neurite outgrowth and excitatory synapse maintenance. In the present study, we report on rare variants (one nonsense and six missense variants) in SLITRK2 on the X chromosome identified by exome sequencing in individuals with neurodevelopmental disorders. Functional studies showed that some variants displayed impaired membrane transport and impaired excitatory synapse-promoting effects. Strikingly, these variations abolished the ability of SLITRK2 wild-type to reduce the levels of the receptor tyrosine kinase TrkB in neurons. Moreover, Slitrk2 conditional knockout mice exhibited impaired long-term memory and abnormal gait, recapitulating a subset of clinical features of patients with SLITRK2 variants. Furthermore, impaired excitatory synapse maintenance induced by hippocampal CA1-specific cKO of Slitrk2 caused abnormalities in spatial reference memory. Collectively, these data suggest that SLITRK2 is involved in X-linked neurodevelopmental disorders that are caused by perturbation of diverse facets of SLITRK2 function. The protein SLITRK2 plays an important role in synaptic communication. This study identifies X-linked SLITRK2 variants that underlie neurodevelopmental disorders by impairing excitatory synapses.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
4.8
作者：
Li, Jun;Han, Wenyan;Lu, Wei
通讯作者：
Lu, Wei
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
16.6
作者：
Batiuk, Mykhailo Y.;Martirosyan, Araks;Holt, Matthew G.
通讯作者：
Holt, Matthew G.
DOI：
10.1073/pnas.2110196119
发表时间：
2022-01-18
影响因子：
11.1
作者：
Kim J;Park D;Seo NY;Yoon TH;Kim GH;Lee SH;Seo J;Um JW;Lee KJ;Ko J
通讯作者：
Ko J