한빛사 논문
Salima El Chehadeh1,2,3,33, Kyung Ah Han4,33, Dongwook Kim4,33, Gyubin Jang4,33, Somayeh Bakhtiari5,6, Dongseok Lim4, Hee Young Kim4, Jinhu Kim4, Hyeonho Kim4, Julia Wynn7, Wendy K. Chung7,8, Giuseppina Vitiello9, Ioana Cutcutache10, Matthew Page10, Jozef Gecz11,12,13, Kelly Harper11,12, Ah-reum Han14, Ho Min Kim14,15, Marja Wessels16, Allan Bayat17,18, Alberto Fernández Jaén19, Angelo Selicorni20, Silvia Maitz21, Arjan P. M. de Brouwer22, Anneke Vulto-van Silfhout22,23, Martin Armstrong24, Joseph Symonds25, Sébastien Küry26,27, Bertrand Isidor26,27, Benjamin Cogné26,27, Mathilde Nizon26,27, Claire Feger28, Jean Muller3,28, Erin Torti29, Dorothy K. Grange30, Marjolaine Willems31, Michael C. Kruer5,6, Jaewon Ko4,*, Amélie Piton2,28,32,* & Ji Won Um4,*
1Service de Génétique Médicale, Institut de Génétique Médicale d’Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Strasbourg, France. 2Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258, CNRS-UMR7104, Université de Strasbourg, IllkirchGraffenstaden, France. 3Laboratoire de Génétique Médicale, UMRS_1112, Institut de Génétique Médicale d’Alsace (IGMA), Université de Strasbourg et INSERM, Strasbourg, France. 4Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea. 5Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, USA. 6Departments of Child Health, Neurology, Cellular & Molecular Medicine and Program in Genetics, University of Arizona College of Medicine, Phoenix, AZ, USA. 7Departments of Pediatrics, Columbia University Medical Center, New York, NY, USA. 8Department of Medicine, Columbia University, New York, NY 10032, USA. 9Department of Molecular Medicine and Medical Biotechnologies, Federico II University Hospital, Via Pansini 5, 80131 Naples, Italy. 10Translational Medicine, UCB Pharma, Slough, UK. 11Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia. 12Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia. 13Women and Kids, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia. 14Center for Biomolecular and Cellular Structure, Institute for Basic Science, Daejeon 34126, Korea. 15Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea. 16Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands. 17Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center, Dianalund, Denmark. 18Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark. 19Department of Pediatrics Neurology, Quirónsalud Hospital & Universidad Europea, Madrid, Spain. 20Department of Pediatrics, Center for Fragile Child, ASST Lariana Sant’Anna Hospital, San Fermo della Battaglia, Como, Italy. 21Fondazione MBBM, Monza, Italy. 22Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands. 23Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands. 24Translational Medicine, UCB Pharma, Braine-l’Alleud, Belgium. 25Paediatric Neurosciences Research Group, Royal Hospital for Children, Queen Elizabeth University Hospitals, Glasgow, UK. 26Service de Génétique Médicale, CHU Nantes, Nantes, France. 27Nantes Université, CNRS, INSERM, l’institut du thorax, F-44000 Nantes, France. 28Laboratoire de Diagnostic Génétique, Institut de Génétique Médicale d’Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Strasbourg, France. 29GeneDx, Gaithersburg, MD 20877, USA. 30Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA. 31Service de Génétique Médicale, Reference Centre AD SOOR, AnDDI-RARE, Inserm U1298, INM, Arnaud de Villeneuve Hospital and University of Montpellier, Montpellier, France. 32Institut Universitaire de France, Paris, France. 33These authors contributed equally: Salima El Chehadeh, Kyung Ah Han, Dongwook Kim, Gyubin Jang.
*Corresponding author.
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.
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