A Cluster of Autism-Associated Variants on X-Linked NLGN4X Functionally Resemble NLGN4Y.

Autor:	Nguyen TA; 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., Wu K; Synapse and Neural Circuit Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA., Pandey S; Synapse and Neural Circuit Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA., Lehr AW; Receptor Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA., Li Y; Protein/Peptide Sequencing Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA., Bemben MA; Receptor Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA., Badger JD 2nd; Receptor Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA., Lauzon JL; Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada., Wang T; Translational Neuroscience Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA., Zaghloul KA; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA., Thurm A; National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA., Jain M; Department of Bone and OI, Kennedy Krieger Institute, Baltimore, MD 21205, USA., Lu W; Synapse and Neural Circuit Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA., Roche KW; Receptor Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: rochek@ninds.nih.gov.
Jazyk:	angličtina
Zdroj:	Neuron [Neuron] 2020 Jun 03; Vol. 106 (5), pp. 759-768.e7. Date of Electronic Publication: 2020 Apr 02.
DOI:	10.1016/j.neuron.2020.03.008
Abstrakt:	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. Competing Interests: Declaration of Interests The authors declare no competing interests. (Published by Elsevier Inc.)
Databáze:	MEDLINE
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