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A Cluster of Autism-Associated Variants on X-Linked NLGN4X Functionally Resemble NLGN4Y.
Neuron ( IF 16.2 ) Pub Date : 2020-04-02 , DOI: 10.1016/j.neuron.2020.03.008
Thien A Nguyen 1 , Kunwei Wu 2 , Saurabh Pandey 2 , Alexander W Lehr 3 , Yan Li 4 , Michael A Bemben 3 , John D Badger 3 , Julie L Lauzon 5 , Tongguang Wang 6 , Kareem A Zaghloul 7 , Audrey Thurm 8 , Mahim Jain 9 , Wei Lu 2 , Katherine W Roche 3
Affiliation  

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.



中文翻译:

X链接NLGN4X上的自闭症相关变体簇在功能上类似于NLGN4Y。

自闭症谱系障碍(ASD)在男性中更为普遍。但是,这种性别偏见的病因尚不十分清楚。X连锁的细胞粘附分子NLGN4X上的许多突变都会导致ASD或智力障碍。NLGN4X是XY对的一部分,其中NLGN4Y共有约97%的序列同源性。使用生物化学,电生理学和成像技术,我们显示NLGN4Y在成熟,表面表达和突触形成中显示出严重的缺陷,该缺陷由NLGN4X的一个氨基酸差异调节。此外,我们发现围绕NLGN4X中关键氨基酸的ASD相关突变簇,以及这些突变表型NLGN4Y。我们表明,NLGN4Y无法补偿在ASD相关的NLGN4X突变中观察到的功能缺陷。总之,我们的数据揭示了与NLGN4X相关的ASD中男性偏倚的潜在病原机制。

更新日期:2020-04-02
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