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단백질 커뮤니케이션 그룹
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SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice

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Title
SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice
Author(s)
El Chehadeh, Salima; Han, Kyung Ah; Kim, Dongwook; Jang, Gyubin; Bakhtiari, Somayeh; Lim, Dongseok; Kim, Hee Young; Kim, Jinhu; Kim, Hyeonho; Wynn, Julia; Chung, Wendy K.; Vitiello, Giuseppina; Cutcutache, Ioana; Page, Matthew; Gecz, Jozef; Harper, Kelly; Ah-Reum Han; Ho Min Kim; Wessels, Marja; Bayat, Allan; Fernandez Jaen, Alberto; Selicorni, Angelo; Maitz, Silvia; de Brouwer, Arjan P. M.; Vulto-van Silfhout, Anneke; Armstrong, Martin; Symonds, Joseph; Kury, Sebastien; Isidor, Bertrand; Cogne, Benjamin; Nizon, Mathilde; Feger, Claire; Muller, Jean; Torti, Erin; Grange, Dorothy K.; Willems, Marjolaine; Kruer, Michael C.; Ko, Jaewon; Piton, Amelie; Um, Ji Won
Publication Date
2022-07
Journal
NATURE COMMUNICATIONS, v.13, no.1
Publisher
NATURE PORTFOLIO
Abstract
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.
URI
https://pr.ibs.re.kr/handle/8788114/12143
DOI
10.1038/s41467-022-31566-z
ISSN
2041-1723
Appears in Collections:
Pioneer Research Center for Biomolecular and Cellular Structure(바이오분자 및 세포구조 연구단) > Protein Communication Group(단백질 커뮤니케이션 그룹) > 1. Journal Papers (저널논문)
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