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

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

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskriftArtikelForskningpeer review


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.

Sider (fra-til)1436-1457
Antal sider22
TidsskriftAmerican Journal of Human Genetics
Udgave nummer8
StatusUdgivet - 4 aug. 2022

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Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.


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