A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export

Chen Zhang, Jeff M. Milunsky, Stephanie Newton, Jaewon Ko, Geping Zhao, Tom A. Maher, Helen Tager-Flusberg, Marc F. Bolliger, Alice S. Carter, Antony A. Boucard, Craig M. Powell, Thomas C. Südhof

Research output: Contribution to journalArticle

107 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)10843-10854
Number of pages12
JournalJournal of Neuroscience
Volume29
Issue number35
DOIs
StatePublished - Sep 2 2009

Fingerprint

Missense Mutation
Autistic Disorder
Endoplasmic Reticulum
Synapses
Mutation
Siblings
HEK293 Cells
COS Cells
Cell Adhesion Molecules
Amino Acid Substitution
Glycosylation
Point Mutation
Germ Cells
Protein Isoforms
Parents
Mothers
Neurons
Genes
Autism Spectrum Disorder
Proteins

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Zhang, C., Milunsky, J. M., Newton, S., Ko, J., Zhao, G., Maher, T. A., ... Südhof, T. C. (2009). A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export. Journal of Neuroscience, 29(35), 10843-10854. https://doi.org/10.1523/JNEUROSCI.1248-09.2009

A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export. / Zhang, Chen; Milunsky, Jeff M.; Newton, Stephanie; Ko, Jaewon; Zhao, Geping; Maher, Tom A.; Tager-Flusberg, Helen; Bolliger, Marc F.; Carter, Alice S.; Boucard, Antony A.; Powell, Craig M.; Südhof, Thomas C.

In: Journal of Neuroscience, Vol. 29, No. 35, 02.09.2009, p. 10843-10854.

Research output: Contribution to journalArticle

Zhang, C, Milunsky, JM, Newton, S, Ko, J, Zhao, G, Maher, TA, Tager-Flusberg, H, Bolliger, MF, Carter, AS, Boucard, AA, Powell, CM & Südhof, TC 2009, 'A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export', Journal of Neuroscience, vol. 29, no. 35, pp. 10843-10854. https://doi.org/10.1523/JNEUROSCI.1248-09.2009
Zhang, Chen ; Milunsky, Jeff M. ; Newton, Stephanie ; Ko, Jaewon ; Zhao, Geping ; Maher, Tom A. ; Tager-Flusberg, Helen ; Bolliger, Marc F. ; Carter, Alice S. ; Boucard, Antony A. ; Powell, Craig M. ; Südhof, Thomas C. / A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export. In: Journal of Neuroscience. 2009 ; Vol. 29, No. 35. pp. 10843-10854.
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