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.

ADGRL1（latrophilin 1）是一种充分表征的粘附 G 蛋白偶联受体，与突触发育、成熟和活动有关。然而，ADGRL1 在人类疾病中的作用一直难以捉摸。在这里，我们描述了 10 个具有可变神经发育特征的个体，包括发育迟缓、智力障碍、注意力缺陷多动症和自闭症谱系障碍以及癫痫，所有ADGRL1变异都是杂合的。在体外，在神经母细胞瘤细胞中表达的人类ADGRL1变体显示出错误的配体诱导的细胞内 Ca ²⁺流入调节，与单倍体不足一致。体内, Adgrl1在小鼠中被敲除并研究了两种遗传背景。在非允许的背景下，携带杂合子Adgrl1无效等位基因的小鼠表现出神经和发育异常，而纯合子小鼠则无法存活。在宽松的背景下，敲除动物也以亚孟德尔比率出生，但许多Adgrl1缺失小鼠在妊娠期存活下来并达到了成年期。Adgrl1 ^-/-小鼠表现出刻板行为、性功能障碍、运动的双峰极端、增强的惊吓反射和减弱的前脉冲抑制，这对利培酮有反应。离体突触制剂显示多巴胺、乙酰胆碱和谷氨酸的自发胞吐增加，但Adgrl1^-/-神经元在体外形成的突触很差。总体而言，我们的研究结果表明， ADGRL1单倍体不足会导致小鼠和人类出现持续的发育、神经和行为异常。