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

被引：0

作者：

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

机构：

[1] Hôpitaux Universitaires de Strasbourg,Service de Génétique Médicale, Institut de Génétique Médicale d’Alsace (IGMA)

[2] Université de Strasbourg,Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258, CNRS

[3] Université de Strasbourg et INSERM,UMR7104

[4] Daegu Gyeongbuk Institute of Science and Technology (DGIST),Laboratoire de Génétique Médicale, UMRS_1112, Institut de Génétique Médicale d’Alsace (IGMA)

[5] Phoenix Children’s Hospital,Department of Brain Sciences

[6] University of Arizona College of Medicine,Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute

[7] Columbia University Medical Center,Departments of Child Health, Neurology, Cellular & Molecular Medicine and Program in Genetics

[8] Columbia University,Departments of Pediatrics

[9] Federico II University Hospital,Department of Medicine

[10] UCB Pharma,Department of Molecular Medicine and Medical Biotechnologies

[11] The University of Adelaide,Translational Medicine

[12] The University of Adelaide,Adelaide Medical School, Faculty of Health and Medical Sciences

[13] South Australian Health and Medical Research Institute,Robinson Research Institute

[14] Institute for Basic Science,Women and Kids

[15] Korea Advanced Institute of Science and Technology (KAIST),Center for Biomolecular and Cellular Structure

[16] Erasmus University Medical Center,Graduate School of Medical Science and Engineering

[17] Danish Epilepsy Center,Department of Clinical Genetics

[18] University of Southern Denmark,Department of Epilepsy Genetics and Personalized Medicine

[19] Quirónsalud Hospital & Universidad Europea,Institute for Regional Health Services

[20] ASST Lariana Sant’Anna Hospital,Department of Pediatrics Neurology

[21] San Fermo della Battaglia,Department of Pediatrics, Center for Fragile Child

[22] Fondazione MBBM,Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior

[23] Radboud University Medical Center,Department of Clinical Genetics

[24] Maastricht University Medical Centre,Paediatric Neurosciences Research Group, Royal Hospital for Children

[25] Translational Medicine,Service de Génétique Médicale

[26] UCB Pharma,Laboratoire de Diagnostic Génétique, Institut de Génétique Médicale d’Alsace (IGMA)

[27] Queen Elizabeth University Hospitals,Division of Genetics and Genomic Medicine, Department of Pediatrics

[28] CHU Nantes,Service de Génétique Médicale, Reference Centre AD SOOR, AnDDI

[29] Nantes Université,RARE

[30] CNRS,undefined

[31] INSERM,undefined

[32] l’institut du thorax,undefined

[33] Hôpitaux Universitaires de Strasbourg,undefined

[34] GeneDx,undefined

[35] Washington University School of Medicine,undefined

[36] Inserm U1298,undefined

[37] INM,undefined

[38] Arnaud de Villeneuve Hospital and University of Montpellier,undefined

[39] Institut Universitaire de France,undefined

来源：

Nature Communications | / 13卷

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摘要：

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.

引用

共 89 条

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