在自闭症中鉴定到的罕见 NRXN1 错义变异体干扰了蛋白质降解和果蝇的睡眠。
Rare NRXN1 missense variants identified in autism interfered protein degradation and Drosophila sleeping.
机构信息
Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, China; Center for Medical Genetics and Hunan Provincial Key Laboratory for Medical Genetics, School of Life Sciences, Central South University, Changsha, China; Key Laboratory of Otolaryngology Major Disease Research of Hunan Province, Xiangya Hospital, Central South University, Changsha, China.
Center for Medical Genetics and Hunan Provincial Key Laboratory for Medical Genetics, School of Life Sciences, Central South University, Changsha, China; Key Laboratory of Animal Models for Human Diseases of Hunan Province, Central South University, Changsha, China.
出版信息
J Psychiatr Res. 2021 Nov;143:113-122. doi: 10.1016/j.jpsychires.2021.09.013. Epub 2021 Sep 2.
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，并且与自闭症谱系障碍有关。然而，许多 NRXN1 的罕见遗传性错义变异尚未得到彻底评估。在这里，我们对之前在 ASD 患者中鉴定的三个 NRXN1 错义突变（Y282H、L893V 和 I1135V）进行了体外和果蝇中的功能分析。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 会导致异常的昼夜节律和睡眠行为，而三个突变蛋白导致的表型更轻微，这表明这些突变可能会使 NRXN1 的功能略有改变。这些发现强调了在自闭症患者中鉴定的罕见 NRXN1 错义变异的功能作用，并为我们提供了线索，以更好地理解包括人类在内的其他生物体异常昼夜节律和睡眠行为的发病机制。
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