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

Salima El Chehadeh (1, 2, 3) , Kyung Ah Han , Dongwook Kim , Gyubin Jang , Somayeh Bakhtiari , Dongseok Lim , Hee Young Kim , Jinhu Kim , Hyeonho Kim , Julia Wynn , Wendy K. Chung , Giuseppina Vitiello , Ioana Cutcutache , Matthew Page , Jozef Gecz , Kelly Harper , Ah-Reum Han , Ho Min Kim , Marja Wessels , Allan Bayat , Alberto Fernández Jaén , Angelo Selicorni , Silvia Maitz , Arjan P. M. de Brouwer , Anneke Vulto-Van Silfhout , Martin Armstrong , Joseph Symonds , Sébastien Küry (4) , Bertrand Isidor (4) , Benjamin Cogné (4) , Mathilde Nizon (4) , Claire Feger (5, 3) , Jean Muller (2, 5, 3) , Erin Torti , Dorothy K. Grange , Marjolaine Willems (6) , Michael C. Kruer , Jaewon Ko , Amélie Piton (1, 3, 7) , Ji Won Um

1 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
2 LGM - Laboratoire de Génétique Médicale
3 HUS - Les Hôpitaux Universitaires de Strasbourg
4 ITX-lab - ITX-lab unité de recherche de l'institut du thorax UMR1087 UMR6291
5 Institut de génétique médicale
6 INM - Institut des Neurosciences de Montpellier
7 IUF - Institut universitaire de France

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.

Domaines: Neurobiologie; Génétique humaine; Sciences cognitives

Salima El Chehadeh, Kyung Ah Han, Dongwook Kim, Gyubin Jang, Somayeh Bakhtiari, et al.. SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice. Nature Communications, 2022, 13 (1), pp.4112. ⟨10.1038/s41467-022-31566-z⟩. ⟨hal-04225576⟩