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.
We thank Jinha Kim (DGIST, Korea) for technical assistance, Vaidehi Jobanputra (Columbia University, USA) and Lenet Watt Skovstrøm (Amplexa Genetics, Denmark) for genomic analysis. This study was supported by grants from the National Research Foundation of Korea (NRF) funded by the Ministry of Science and Future Planning (2019R1A2C1086048 and 2020R1A4A1019009 to J.W.U.; 2021R1A2C1091863 to J.Ko.), the DGIST R&D Program of the Ministry of Science and ICT (22-CoE-BT-01 to J.Ko. and J.W.U.), Institute for Basic Science (IBS-R030-C1 to H.M.K.), NIH (NS106298 to M.C.K.), and SFARI and JPB Foundation (to W.K.C.).
Publisher Copyright: © 2022, The Author(s).