Fiche publication
Date publication
juillet 2022
Journal
American journal of human genetics
Auteurs
Membres identifiés du Cancéropôle Est :
Pr FAIVRE Laurence
,
Pr PHILIPPE Christophe
,
Dr NAMBOT Sophie
,
Mr DUFFOURD Yannis
,
Pr THAUVIN-ROBINET Christel
,
Dr MAZEL Benoît
Tous les auteurs :
Vitobello A, Mazel B, Lelianova VG, Zangrandi A, Petitto E, Suckling J, Salpietro V, Meyer R, Elbracht M, Kurth I, Eggermann T, Benlaouer O, Lall G, Tonevitsky AG, Scott DA, Chan KM, Rosenfeld JA, Nambot S, Safraou H, Bruel AL, Denommé-Pichon AS, Tran Mau-Them F, Philippe C, Duffourd Y, Guo H, Petersen AK, Granger L, Crunk A, Bayat A, Striano P, Zara F, Scala M, Thomas Q, Delahaye A, de Sainte Agathe JM, Buratti J, Kozlov SV, Faivre L, Thauvin-Robinet C, Ushkaryov Y
Lien Pubmed
Résumé
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 Ca 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.
Mots clés
ADGRL1, ADHD, ASD, Adgrl1 knockout mice, attention deficit hyperactivity disorder, autism spectrum disorder, developmental delay, epilepsy, intellectual disability, malfunctional behavior in mice, neuropsychiatric disorders, variable expressivity
Référence
Am J Hum Genet. 2022 07 29;:
