Relevance to Autism

De novo missense variants in the ADGRL1 gene were identified in two ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014, while a rare de novo nonsense variant in this gene was identified in an ASD proband from the Study of Autism Genetics Exploration (SAGE) collection in Guo et al., 2019. Vitobello et al., 2022 described ten individuals from 9 families with heterozygous variants in the ADGRL1 gene, including in the ASD proband originally reported in Guo et al., 2019, that presented with variable neurodevelopmental features includigng developmental delay, intellectual disability, autism spectrum disorder, ADHD, and epilepsy; ADGRL1 variants expressed in vitro in mouse neuroblastoma cells displayed abnormalities in ligand-induced regulation of intracellular calcium influx that were consistent with haploinsufficiency. Furthermore, Vitobello et al., 2022 showed that mice carrying a heterozygous Adgrl1 null allele on a non-permissive background exhibited neurological and developmental abnormalities, whereas Agrl1 -/- mice on a permissive background demonstrated stereotypic behaviors, sexual dysfunction, bimodal extremes of locomotion, augmented startle reflex, and attenuated pre-pulse inhibition.

Molecular Function

Calcium-independent receptor of high affinity for alpha-latrotoxin, an excitatory neurotoxin present in black widow spider venom which triggers massive exocytosis from neurons and neuroendocrine cells. Receptor for TENM2 that mediates heterophilic synaptic cell-cell contact and postsynaptic specialization. Receptor probably implicated in the regulation of exocytosis.

External Links

References