title: A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export.
abstract: Neuroligins (NLs) are postsynaptic cell-adhesion molecules essential for normal synapse function. Mutations in neuroligin-4 (NL4) (gene symbol: NLGN4) have been reported in some patients with autism spectrum disorder (ASD) and other neurodevelopmental impairments. However, the low frequency of NL4 mutations and the limited information about the affected patients and the functional consequences of their mutations cast doubt on the causal role of NL4 mutations in these disorders. Here, we describe two brothers with classical ASD who carry a single amino-acid substitution in NL4 (R87W). This substitution was absent from the brothers' asymptomatic parents, suggesting that it arose in the maternal germ line. R87 is conserved in all NL isoforms, and the R87W substitution is not observed in control individuals. At the protein level, the R87W substitution impaired glycosylation processing of NL4 expressed in HEK293 and COS cells, destabilized NL4, caused NL4 retention in the endoplasmic reticulum in non-neuronal cells and neurons, and blocked NL4 transport to the cell surface. As a result, the R87W substitution inactivated the synapse-formation activity of NL4 and abolished the functional effect of NL4 on synapse strength. Viewed together, these observations suggest that a point mutation in NL4 can cause ASD by a loss-of-function mechanism.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University, Palo Alto, California 94304, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Milunsky
authors.forename: Stephanie
authors.initials: S
authors.lastname: Newton
authors.forename: Jaewon
authors.initials: J
authors.lastname: Ko
authors.forename: Geping
authors.initials: G
authors.lastname: Zhao
authors.forename: Tom A
authors.initials: TA
authors.lastname: Maher
authors.forename: Helen
authors.initials: H
authors.lastname: Tager-Flusberg
authors.forename: Marc F
authors.initials: MF
authors.lastname: Bolliger
authors.forename: Alice S
authors.initials: AS
authors.lastname: Carter
authors.forename: Antony A
authors.initials: AA
authors.lastname: Boucard
authors.forename: Craig M
authors.initials: CM
authors.lastname: Powell
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001120:Arginine / Q000235:genetics; D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism; D019556:COS Cells; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal; D002460:Cell Line; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D017510:Protein Folding; D021381:Protein Transport / Q000235:genetics; D014364:Tryptophan / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; D008565:Membrane Proteins; C430845:NLGN4X protein, human; D014364:Tryptophan; D001120:Arginine