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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

Authors :
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 Bruel
Anne-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
Source :
Am J Hum Genet
Publication Year :
2022
Publisher :
Cell Press, 2022.

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 10 individuals with variable neurodevelopmental features including developmental delay, intellectual disability, attention deficit hyperactivity and autism spectrum disorders, and epilepsy, all featuring heterozygous 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, the null allele also appeared at sub-Mendelian frequency, but many Adgrl1 null mice survived the gestation and reached adulthood. The 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.

Details

Language :
English
ISSN :
00029297
Database :
OpenAIRE
Journal :
Am J Hum Genet
Accession number :
edsair.doi.dedup.....6dd4a155399f4d282e04e1b905624a55