TY - JOUR
T1 - ADGRL1 haploinsufficiency causes a variable spectrum of neurodevelopmental disorders in humans and alters synaptic activity and behavior in a mouse model
AU - Vitobello, Antonio
AU - Mazel, Benoit
AU - Lelianova, Vera G.
AU - Zangrandi, Alice
AU - Petitto, Evelina
AU - Suckling, Jason
AU - Salpietro, Vincenzo
AU - Meyer, Robert
AU - Elbracht, Miriam
AU - Kurth, Ingo
AU - Eggermann, Thomas
AU - Benlaouer, Ouafa
AU - Lall, Gurprit
AU - Tonevitsky, Alexander G.
AU - Scott, Daryl A.
AU - Chan, Katie M.
AU - Rosenfeld, Jill A.
AU - Nambot, Sophie
AU - Safraou, Hana
AU - Bruel, Ange Line
AU - Denommé-Pichon, Anne Sophie
AU - Tran Mau-Them, Frédéric
AU - Philippe, Christophe
AU - Duffourd, Yannis
AU - Guo, Hui
AU - Petersen, Andrea K.
AU - Granger, Leslie
AU - Crunk, Amy
AU - Bayat, Allan
AU - Striano, Pasquale
AU - Zara, Federico
AU - Scala, Marcello
AU - Thomas, Quentin
AU - Delahaye, Andrée
AU - de Sainte Agathe, Jean Madeleine
AU - Buratti, Julien
AU - Kozlov, Serguei V.
AU - Faivre, Laurence
AU - Thauvin-Robinet, Christel
AU - Ushkaryov, Yuri
N1 - Publisher Copyright:
© 2022 American Society of Human Genetics
PY - 2022/8/4
Y1 - 2022/8/4
N2 - 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.
AB - 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.
KW - ADGRL1
KW - Adgrl1 knockout mice
KW - ADHD
KW - ASD
KW - attention deficit hyperactivity disorder
KW - autism spectrum disorder
KW - developmental delay
KW - epilepsy
KW - intellectual disability
KW - malfunctional behavior in mice
KW - neuropsychiatric disorders
KW - variable expressivity
U2 - 10.1016/j.ajhg.2022.06.011
DO - 10.1016/j.ajhg.2022.06.011
M3 - Journal article
C2 - 35907405
AN - SCOPUS:85135175573
SN - 0002-9297
VL - 109
SP - 1436
EP - 1457
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 8
ER -