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ADGRL1 haploinsufficiency causes a variable spectrum of neurodevelopmental disorders in humans and alters synaptic activity and behavior in a mouse model

  1. Author:
    Vitobello, Antonio
    Mazel, Benoit
    Lelianova, Vera G
    Zangrandi, Alice
    Petitto, Evelina
    Suckling, Jason
    Salpietro, Vincenzo
    Meyer, Robert
    Elbracht, Miriam
    Kurth, Ingo
    Eggermann, Thomas
    Benlaouer, Ouafa
    Lall, Gurprit
    Tonevitsky, Alexander G
    Scott, Daryl A
    Chan, Katie M
    Rosenfeld, Jill A
    Nambot, Sophie
    Safraou, Hana
    Bruel, Ange-Line
    Denommé-Pichon, Anne-Sophie
    Tran Mau-Them, Frédéric
    Philippe, Christophe
    Duffourd, Yannis
    Guo, Hui
    Petersen, Andrea K
    Granger, Leslie
    Crunk, Amy
    Bayat, Allan
    Striano, Pasquale
    Zara, Federico
    Scala, Marcello
    Thomas, Quentin
    Delahaye, Andrée
    de Sainte Agathe, Jean-Madeleine
    Buratti, Julien
    Kozlov,Serguei
    Faivre, Laurence
    Thauvin-Robinet, Christel
    Ushkaryov, Yuri

  2. Author Address

    Inserm UMR1231 GAD, G 233;n 233;tique des Anomalies du D 233;veloppement, F 233;d 233;ration Hospitalo-Universitaire M 233;decine Translationnelle et Anomalies du D 233;veloppement (FHU TRANSLAD), CHU Dijon Bourgogne - Universit 233; de Bourgogne, Dijon, France; UF Innovation en diagnostic g 233;nomique des maladies rares, CHU Dijon Bourgogne, Dijon, France. Electronic address: antonio.vitobello@u-bourgogne.fr., Inserm UMR1231 GAD, G 233;n 233;tique des Anomalies du D 233;veloppement, F 233;d 233;ration Hospitalo-Universitaire M 233;decine Translationnelle et Anomalies du D 233;veloppement (FHU TRANSLAD), CHU Dijon Bourgogne - Universit 233; de Bourgogne, Dijon, France; UF Innovation en diagnostic g 233;nomique des maladies rares, CHU Dijon Bourgogne, Dijon, France; Centre de G 233;n 233;tique et Centre de R 233;f 233;rence Anomalies du D 233;veloppement et Syndromes Malformatifs, FHU TRANSLAD - CHU Dijon Bourgogne, Dijon, France., Medway School of Pharmacy, University of Kent, Anson Building, Central Avenue, Chatham ME4 4TB, UK; Department of Life Sciences, Imperial College London, London, UK., Medway School of Pharmacy, University of Kent, Anson Building, Central Avenue, Chatham ME4 4TB, UK., Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy., Institute of Human Genetics, Medical Faculty, RWTH Aachen, Aachen, Germany., Faculty of Biology and Biotechnology, HSE University, Moscow, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997, Moscow, Russia., Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Inserm UMR1231 GAD, G 233;n 233;tique des Anomalies du D 233;veloppement, F 233;d 233;ration Hospitalo-Universitaire M 233;decine Translationnelle et Anomalies du D 233;veloppement (FHU TRANSLAD), CHU Dijon Bourgogne - Universit 233; de Bourgogne, Dijon, France; Centre de G 233;n 233;tique et Centre de R 233;f 233;rence Anomalies du D 233;veloppement et Syndromes Malformatifs, FHU TRANSLAD - CHU Dijon Bourgogne, Dijon, France., Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA., Randall Children 39;s Hospital, Portland, OR, USA., GeneDx, Inc., Gaithersburg, MD, USA., Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Dianalund, Denmark; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark., Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy; Medical Genetics Unit, IRCSS Istituto Giannina Gastini, Genoa, Italy., Inserm UMR1231 GAD, G 233;n 233;tique des Anomalies du D 233;veloppement, F 233;d 233;ration Hospitalo-Universitaire M 233;decine Translationnelle et Anomalies du D 233;veloppement (FHU TRANSLAD), CHU Dijon Bourgogne - Universit 233; de Bourgogne, Dijon, France; Centre de G 233;n 233;tique et Centre de R 233;f 233;rence D 233;ficiences Intellectuelles de causes rares, FHU TRANSLAD - CHU Dijon Bourgogne, Dijon, France., UF m 233;decine g 233;nomique et g 233;n 233;tique clinique, H 244;pital Jean Verdier, H 244;pitaux Universitaires de Paris Seine Saint Denis, AP-HP, Bondy, France; UFR de Sant 233; M 233;decine et Biologie humaine, Universit 233; Sorbonne Paris Nord, Bodigny, France; NeuroDiderot UMR 1141, Inserm, FHU I2-D2, Universit 233; de Paris, Paris, France., D 233;partement de G 233;n 233;tique M 233;dicale, H 244;pital Piti 233;-Salp 234;tri 232;re, AP-HP, Sorbonne Universit 233;, Paris, France., Center for Advanced Preclinical Research, National Cancer Institute, Frederick, MD, USA., Inserm UMR1231 GAD, G 233;n 233;tique des Anomalies du D 233;veloppement, F 233;d 233;ration Hospitalo-Universitaire M 233;decine Translationnelle et Anomalies du D 233;veloppement (FHU TRANSLAD), CHU Dijon Bourgogne - Universit 233; de Bourgogne, Dijon, France; UF Innovation en diagnostic g 233;nomique des maladies rares, CHU Dijon Bourgogne, Dijon, France; Centre de G 233;n 233;tique et Centre de R 233;f 233;rence D 233;ficiences Intellectuelles de causes rares, FHU TRANSLAD - CHU Dijon Bourgogne, Dijon, France., Medway School of Pharmacy, University of Kent, Anson Building, Central Avenue, Chatham ME4 4TB, UK; Department of Life Sciences, Imperial College London, London, UK; Faculty of Biology and Biotechnology, HSE University, Moscow, Russia. Electronic address: y.ushkaryov@kent.ac.uk.,
    1. Year: 2022
    2. Date: Jul 29
    3. Epub Date: 2022 07 29
  2. Journal: American Journal of Human Genetics
    1. 109
    2. 8
    3. Pages: 1436-1457.
  4. Type of Article: Article
  1. Abstract:

    ADGRL1 (latrophilin 1), a well-characterized adhesion G protein-coupled receptor, has been implicated in synaptic development, maturation, and activity. However, the role of ADGRL1 in human disease has been elusive. Here, we describe ten individuals with variable neurodevelopmental features including developmental delay, intellectual disability, attention deficit hyperactivity and autism spectrum disorders, and epilepsy, all heterozygous for variants in ADGRL1. In vitro, human ADGRL1 variants expressed in neuroblastoma cells showed faulty ligand-induced regulation of intracellular Ca2+ influx, consistent with haploinsufficiency. In vivo, Adgrl1 was knocked out in mice and studied on two genetic backgrounds. On a non-permissive background, mice carrying a heterozygous Adgrl1 null allele exhibited neurological and developmental abnormalities, while homozygous mice were non-viable. On a permissive background, knockout animals were also born at sub-Mendelian ratios, but many Adgrl1 null mice survived gestation and reached adulthood. Adgrl1-/- mice demonstrated stereotypic behaviors, sexual dysfunction, bimodal extremes of locomotion, augmented startle reflex, and attenuated pre-pulse inhibition, which responded to risperidone. Ex vivo synaptic preparations displayed increased spontaneous exocytosis of dopamine, acetylcholine, and glutamate, but Adgrl1-/- neurons formed synapses in vitro poorly. Overall, our findings demonstrate that ADGRL1 haploinsufficiency leads to consistent developmental, neurological, and behavioral abnormalities in mice and humans. Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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  2. DOI: 10.1016/j.ajhg.2022.06.011
  3. PMID: 35907405
  4. PII : S0002-9297(22)00264-6

Library Notes

  1. Fiscal Year: FY2021-2022
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