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

Salima El Chehadeh, 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. Brouwer, Anneke Vulto- van Silfhout, Martin Armstrong, Joseph Symonds, Sébastien Küry, Bertrand Isidor, Benjamin Cogné, Mathilde Nizon, Claire Feger, Jean Muller, Erin Torti, Dorothy K. Grange, Marjolaine Willems, Michael C. Kruer, Jaewon Ko (), Amélie Piton () and Ji Won Um ()
Additional contact information
Salima El Chehadeh: Hôpitaux Universitaires de Strasbourg
Kyung Ah Han: Daegu Gyeongbuk Institute of Science and Technology (DGIST)
Dongwook Kim: Daegu Gyeongbuk Institute of Science and Technology (DGIST)
Gyubin Jang: Daegu Gyeongbuk Institute of Science and Technology (DGIST)
Somayeh Bakhtiari: Phoenix Children’s Hospital
Dongseok Lim: Daegu Gyeongbuk Institute of Science and Technology (DGIST)
Hee Young Kim: Daegu Gyeongbuk Institute of Science and Technology (DGIST)
Jinhu Kim: Daegu Gyeongbuk Institute of Science and Technology (DGIST)
Hyeonho Kim: Daegu Gyeongbuk Institute of Science and Technology (DGIST)
Julia Wynn: Columbia University Medical Center
Wendy K. Chung: Columbia University Medical Center
Giuseppina Vitiello: Federico II University Hospital
Ioana Cutcutache: UCB Pharma
Matthew Page: UCB Pharma
Jozef Gecz: The University of Adelaide
Kelly Harper: The University of Adelaide
Ah-reum Han: Institute for Basic Science
Ho Min Kim: Institute for Basic Science
Marja Wessels: Erasmus University Medical Center
Allan Bayat: Danish Epilepsy Center
Alberto Fernández Jaén: Quirónsalud Hospital & Universidad Europea
Angelo Selicorni: ASST Lariana Sant’Anna Hospital, San Fermo della Battaglia
Silvia Maitz: Fondazione MBBM
Arjan P. M. Brouwer: Radboud University Medical Center
Anneke Vulto- van Silfhout: Radboud University Medical Center
Martin Armstrong: Translational Medicine, UCB Pharma
Joseph Symonds: Queen Elizabeth University Hospitals
Sébastien Küry: CHU Nantes
Bertrand Isidor: CHU Nantes
Benjamin Cogné: CHU Nantes
Mathilde Nizon: CHU Nantes
Claire Feger: Hôpitaux Universitaires de Strasbourg
Jean Muller: Université de Strasbourg et INSERM
Erin Torti: GeneDx
Dorothy K. Grange: Washington University School of Medicine
Marjolaine Willems: Inserm U1298, INM, Arnaud de Villeneuve Hospital and University of Montpellier
Michael C. Kruer: Phoenix Children’s Hospital
Jaewon Ko: Daegu Gyeongbuk Institute of Science and Technology (DGIST)
Amélie Piton: Université de Strasbourg
Ji Won Um: Daegu Gyeongbuk Institute of Science and Technology (DGIST)

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31566-z

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