Receptor Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA; Department of Pharmacology and Physiology, Georgetown University, Washington DC 20057, USA.
Synapse and Neural Circuit Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Neuron. 2020 Jun 3;106(5):759-768.e7. doi: 10.1016/j.neuron.2020.03.008. Epub 2020 Apr 2.
Autism spectrum disorder (ASD) is more prevalent in males; however, the etiology for this sex bias is not well understood. Many mutations on X-linked cell adhesion molecule NLGN4X result in ASD or intellectual disability. NLGN4X is part of an X-Y pair, with NLGN4Y sharing ∼97% sequence homology. Using biochemistry, electrophysiology, and imaging, we show that NLGN4Y displays severe deficits in maturation, surface expression, and synaptogenesis regulated by one amino acid difference with NLGN4X. Furthermore, we identify a cluster of ASD-associated mutations surrounding the critical amino acid in NLGN4X, and these mutations phenocopy NLGN4Y. We show that NLGN4Y cannot compensate for the functional deficits observed in ASD-associated NLGN4X mutations. Altogether, our data reveal a potential pathogenic mechanism for male bias in NLGN4X-associated ASD.
自闭症谱系障碍（ASD）在男性中更为普遍；然而，这种性别偏差的病因尚不清楚。许多 X 连锁细胞黏附分子 NLGN4X 的突变导致 ASD 或智力障碍。NLGN4X 是 X-Y 对的一部分，NLGN4Y 共享约 97%的序列同源性。我们使用生物化学、电生理学和成像技术表明，NLGN4Y 在成熟、表面表达和受一个氨基酸差异调节的突触发生方面存在严重缺陷，而 NLGN4X 则存在这种差异。此外，我们在 NLGN4X 中的关键氨基酸周围发现了一组与 ASD 相关的突变簇，这些突变与 NLGN4Y 相似。我们表明，NLGN4Y 不能弥补与 ASD 相关的 NLGN4X 突变中观察到的功能缺陷。总的来说，我们的数据揭示了 NLGN4X 相关 ASD 中男性偏倚的潜在致病机制。
