NRXN1 is involved in synaptogenesis and have been implicated in Autism spectrum disorders. However, many rare inherited missense variants of NRXN1 have not been thoroughly evaluated. Here, functional analyses in vitro and in Drosophila of three NRXN1 missense mutations, Y282H, L893V, and I1135V identified in ASD patients in our previous study were performed. Our results showed these three mutations interfered protein degradation compared with NRXN1-WT protein. Expressing human NRXN1 in Drosophila could lead to abnormal circadian rhythm and sleep behavior, and three mutated proteins caused milder phenotypes, indicating the mutations may change the function of NRXN1 slightly. These findings highlight the functional role of rare NRXN1 missense variants identified in autism patients, and provide clues for us to better understand the pathogenesis of abnormal circadian rhythm and sleep behavior of other organisms, including humans.

NRXN1参与突触发生并与自闭症谱系障碍有关。然而，许多罕见的NRXN1遗传错义变体尚未得到彻底评估。在这里，对我们先前研究中在 ASD 患者中鉴定的三种NRXN1错义突变 Y282H 、 L893V 和 I1135V 进行了体外和果蝇的功能分析。我们的结果表明，与 NRXN1-WT 蛋白相比，这三个突变干扰了蛋白质降解。在果蝇中表达人类 NRXN1可导致昼夜节律和睡眠行为异常，三种突变蛋白引起较温和的表型，表明这些突变可能会改变果蝇的功能。NRXN1略。这些发现突出了在自闭症患者中发现的罕见NRXN1错义变异的功能作用，并为我们更好地了解包括人类在内的其他生物的昼夜节律异常和睡眠行为的发病机制提供了线索。