ADGRL1 haploinsufficiency causes a variable spectrum of neurodevelopmental disorders in humans and alters synaptic activity and behavior in a mouse model
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | American Journal of Human Genetics |
| Vol/bind | 109 |
| Udgave nummer | 8 |
| Sider (fra-til) | 1436-1457 |
| Antal sider | 22 |
| ISSN | 0002-9297 |
| DOI | |
| Status | Udgivet - 2022 |
| Eksternt udgivet | Ja |
Bibliografisk note
Funding Information:
We thank the individuals and their families for their participation. We thank the Integragen society and the French National Center of Human Genomics Research (CNRGH) for exome analysis in some cases. We thank Evan E. Eichler and his laboratory for sharing clinical data for individual 5. This work was supported by grants from the Regional Council of Burgundy (PARI) and the European Regional Development Fund (FEDER) (to C.T.-R.). This work was also in part supported by Wellcome Trust Project Grants GR074359MA and WT083199MF, Biotechnology and Biological Sciences Research Council Core Support Grants BBD523078 and BBF0083091, and core funding from the University of Kent School of Pharmacy (to Y.U.). The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories. A.C. is an employee of GeneDx, Inc.
Funding Information:
We thank the individuals and their families for their participation. We thank the Integragen society and the French National Center of Human Genomics Research (CNRGH) for exome analysis in some cases. We thank Evan E. Eichler and his laboratory for sharing clinical data for individual 5. This work was supported by grants from the Regional Council of Burgundy (PARI) and the European Regional Development Fund ( FEDER) (to C.T.-R.) . This work was also in part supported by Wellcome Trust Project Grants GR074359MA and WT083199MF , Biotechnology and Biological Sciences Research Council Core Support Grants BBD523078 and BBF0083091 , and core funding from the University of Kent School of Pharmacy (to Y.U.).
Publisher Copyright:
© 2022 American Society of Human Genetics
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