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. de 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; Ji Won Um

doi:10.1038/s41467-022-31566-z

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 BayatAlberto Fernández Jaén, Angelo Selicorni, Silvia Maitz, Arjan P.M. de 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^*, Ji Won Um

^*Corresponding author for this work

Clinical Genetics

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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.

Original language	English
Article number	4112
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-31566-z
Publication status	Published - 15 Jul 2022

Bibliographical note

Acknowledgements:
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).

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El Chehadeh, S., Han, K. A., Kim, D., Jang, G., Bakhtiari, S., Lim, D., Kim, H. Y., Kim, J., Kim, H., Wynn, J., Chung, W. K., Vitiello, G., Cutcutache, I., Page, M., Gecz, J., Harper, K., Han, A. R., Kim, H. M., Wessels, M., ... Um, J. W. (2022). SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice. Nature Communications, 13(1), Article 4112. https://doi.org/10.1038/s41467-022-31566-z

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title = "SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice",

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.",

author = "{El Chehadeh}, Salima and Han, {Kyung Ah} and Dongwook Kim and Gyubin Jang and Somayeh Bakhtiari and Dongseok Lim and Kim, {Hee Young} and Jinhu Kim and Hyeonho Kim and Julia Wynn and Chung, {Wendy K.} and Giuseppina Vitiello and Ioana Cutcutache and Matthew Page and Jozef Gecz and Kelly Harper and Han, {Ah reum} and Kim, {Ho Min} and Marja Wessels and Allan Bayat and Ja{\'e}n, {Alberto Fern{\'a}ndez} and Angelo Selicorni and Silvia Maitz and {de Brouwer}, {Arjan P.M.} and Silfhout, {Anneke Vulto van} and Martin Armstrong and Joseph Symonds and S{\'e}bastien K{\"u}ry and Bertrand Isidor and Benjamin Cogn{\'e} and Mathilde Nizon and Claire Feger and Jean Muller and Erin Torti and Grange, {Dorothy K.} and Marjolaine Willems and Kruer, {Michael C.} and Jaewon Ko and Am{\'e}lie Piton and Um, {Ji Won}",

note = "Acknowledgements: We thank Jinha Kim (DGIST, Korea) for technical assistance, Vaidehi Jobanputra (Columbia University, USA) and Lenet Watt Skovstr{\o}m (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: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = jul,

day = "15",

doi = "10.1038/s41467-022-31566-z",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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El Chehadeh, S, Han, KA, Kim, D, Jang, G, Bakhtiari, S, Lim, D, Kim, HY, Kim, J, Kim, H, Wynn, J, Chung, WK, Vitiello, G, Cutcutache, I, Page, M, Gecz, J, Harper, K, Han, AR, Kim, HM, Wessels, M, Bayat, A, Jaén, AF, Selicorni, A, Maitz, S, de Brouwer, APM, Silfhout, AVV, Armstrong, M, Symonds, J, Küry, S, Isidor, B, Cogné, B, Nizon, M, Feger, C, Muller, J, Torti, E, Grange, DK, Willems, M, Kruer, MC, Ko, J, Piton, A & Um, JW 2022, 'SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice', Nature Communications, vol. 13, no. 1, 4112. https://doi.org/10.1038/s41467-022-31566-z

TY - JOUR

T1 - SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice

AU - El Chehadeh, Salima

AU - Han, Kyung Ah

AU - Kim, Dongwook

AU - Jang, Gyubin

AU - Bakhtiari, Somayeh

AU - Lim, Dongseok

AU - Kim, Hee Young

AU - Kim, Jinhu

AU - Kim, Hyeonho

AU - Wynn, Julia

AU - Chung, Wendy K.

AU - Vitiello, Giuseppina

AU - Cutcutache, Ioana

AU - Page, Matthew

AU - Gecz, Jozef

AU - Harper, Kelly

AU - Han, Ah reum

AU - Kim, Ho Min

AU - Wessels, Marja

AU - Bayat, Allan

AU - Jaén, Alberto Fernández

AU - Selicorni, Angelo

AU - Maitz, Silvia

AU - de Brouwer, Arjan P.M.

AU - Silfhout, Anneke Vulto van

AU - Armstrong, Martin

AU - Symonds, Joseph

AU - Küry, Sébastien

AU - Isidor, Bertrand

AU - Cogné, Benjamin

AU - Nizon, Mathilde

AU - Feger, Claire

AU - Muller, Jean

AU - Torti, Erin

AU - Grange, Dorothy K.

AU - Willems, Marjolaine

AU - Kruer, Michael C.

AU - Ko, Jaewon

AU - Piton, Amélie

AU - Um, Ji Won

N1 - Acknowledgements: 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).

PY - 2022/7/15

Y1 - 2022/7/15

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-022-31566-z

DO - 10.1038/s41467-022-31566-z

M3 - Article

C2 - 35840571

AN - SCOPUS:85134250058

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4112

ER -

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

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