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

Thien A Nguyen; Kunwei Wu; Saurabh Pandey; Alexander W Lehr; Yan Li; Michael A Bemben; John D Badger 2nd; Julie L Lauzon; Tongguang Wang; Kareem A Zaghloul; Audrey Thurm; Mahim Jain; Wei Lu; Katherine W Roche

doi:10.1016/j.neuron.2020.03.008

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

Neuron. 2020 Jun 3;106(5):759-768.e7. doi: 10.1016/j.neuron.2020.03.008. Epub 2020 Apr 2.

Authors

Affiliations

¹ 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.
² Synapse and Neural Circuit Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
³ Receptor Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
⁴ Protein/Peptide Sequencing Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
⁶ Translational Neuroscience Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
⁷ Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
⁸ National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
⁹ Department of Bone and OI, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
¹⁰ Receptor Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: rochek@ninds.nih.gov.

Abstract

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.

Keywords: ASD; ID; X chromosome; Y chromosome; autism; intellectual disability; neuroligin-4X; neuroligin-4Y; sex-bias; synaptic transmission.

Published by Elsevier Inc.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural

MeSH terms

Autism Spectrum Disorder / genetics
Cell Adhesion Molecules, Neuronal / genetics*
Cell Adhesion Molecules, Neuronal / metabolism
Chromosomes, Human, X / genetics*
Chromosomes, Human, Y / genetics*
Female
Genetic Predisposition to Disease
HEK293 Cells
Humans
Induced Pluripotent Stem Cells
Intellectual Disability / genetics
Male
Mutation
Neurons / metabolism*
Protein Transport / genetics

Substances

Cell Adhesion Molecules, Neuronal
NLGN4X protein, human

Grants and funding

ZIA NS003140/ImNIH/Intramural NIH HHS/United States