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The Journal of Neuroscience, September 2, 2009, 29(35):10843-10854; doi:10.1523/JNEUROSCI.1248-09.2009

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Neurobiology of Disease
A Neuroligin-4 Missense Mutation Associated with Autism Impairs Neuroligin-4 Folding and Endoplasmic Reticulum Export

Chen Zhang,^1,3 Jeff M. Milunsky,^8,9 Stephanie Newton,⁸ Jaewon Ko,^1,3 Geping Zhao,⁸ Tom A. Maher,⁸ Helen Tager-Flusberg,¹⁰ Marc F. Bolliger,^1,3 Alice S. Carter,¹⁰ Antony A. Boucard,^1,3 Craig M. Powell,^4,5 and Thomas C. Südhof^1,2,3,6,7

¹Department of Molecular and Cellular Physiology and ²Howard Hughes Medical Institute, Stanford University, Palo Alto, California 94304, Departments of ³Neuroscience, ⁴Neurology, ⁵Psychiatry, and ⁶Molecular Genetics and ⁷Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, and ⁸Center for Human Genetics, ⁹Department of Pediatrics/Genetics and Genomics, and ¹⁰Human Development Program, Boston University School of Medicine, Boston, Massachusetts 02118

Correspondence should be addressed to either of the following: Jeff M. Milunsky, Center for Human Genetics, Boston University School of Medicine, 700 Albany Street, Room W-408, Boston, MA 02118, Email: jmilunsk{at}bu.edu; or Thomas C. Südhof, Howard Hughes Medical Institute, Stanford University, 1050 Arastradero Road, Palo Alto, CA 94304, Email: tcs1{at}stanford.edu

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.

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Received March 13, 2009; revised July 21, 2009; accepted July 23, 2009.

Correspondence should be addressed to either of the following: Jeff M. Milunsky, Center for Human Genetics, Boston University School of Medicine, 700 Albany Street, Room W-408, Boston, MA 02118, Email: jmilunsk{at}bu.edu; or Thomas C. Südhof, Howard Hughes Medical Institute, Stanford University, 1050 Arastradero Road, Palo Alto, CA 94304, Email: tcs1{at}stanford.edu

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