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

Author

Listed:
  • Salima El Chehadeh

    (Hôpitaux Universitaires de Strasbourg
    Université de Strasbourg
    Université de Strasbourg et INSERM)

  • 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
    University of Arizona College of Medicine)

  • 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
    Columbia University)

  • Giuseppina Vitiello

    (Federico II University Hospital)

  • Ioana Cutcutache

    (UCB Pharma)

  • Matthew Page

    (UCB Pharma)

  • Jozef Gecz

    (The University of Adelaide
    The University of Adelaide
    South Australian Health and Medical Research Institute)

  • Kelly Harper

    (The University of Adelaide
    The University of Adelaide)

  • Ah-reum Han

    (Institute for Basic Science)

  • Ho Min Kim

    (Institute for Basic Science
    Korea Advanced Institute of Science and Technology (KAIST))

  • Marja Wessels

    (Erasmus University Medical Center)

  • Allan Bayat

    (Danish Epilepsy Center
    University of Southern Denmark)

  • 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
    Maastricht University Medical Centre)

  • Martin Armstrong

    (Translational Medicine, UCB Pharma)

  • Joseph Symonds

    (Queen Elizabeth University Hospitals)

  • Sébastien Küry

    (CHU Nantes
    Nantes Université, CNRS, INSERM, l’institut du thorax)

  • Bertrand Isidor

    (CHU Nantes
    Nantes Université, CNRS, INSERM, l’institut du thorax)

  • Benjamin Cogné

    (CHU Nantes
    Nantes Université, CNRS, INSERM, l’institut du thorax)

  • Mathilde Nizon

    (CHU Nantes
    Nantes Université, CNRS, INSERM, l’institut du thorax)

  • Claire Feger

    (Hôpitaux Universitaires de Strasbourg)

  • Jean Muller

    (Université de Strasbourg et INSERM
    Hôpitaux Universitaires de Strasbourg)

  • 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
    University of Arizona College of Medicine)

  • Jaewon Ko

    (Daegu Gyeongbuk Institute of Science and Technology (DGIST))

  • Amélie Piton

    (Université de Strasbourg
    Hôpitaux Universitaires de Strasbourg
    Institut Universitaire de France)

  • Ji Won Um

    (Daegu Gyeongbuk Institute of Science and Technology (DGIST))

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.

Suggested Citation

  • 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 , 2022. "SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31566-z
    DOI: 10.1038/s41467-022-31566-z
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