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The Journal of Neuroscience, May 19, 2004, 24(20):4889-4893; doi:10.1523/JNEUROSCI.0468-04.2004

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The Arg451Cys-Neuroligin-3 Mutation Associated with Autism Reveals a Defect in Protein Processing

Davide Comoletti,¹ Antonella De Jaco,¹ Lori L. Jennings,¹ Robyn E. Flynn,¹ Guido Gaietta,² Igor Tsigelny,¹ Mark H. Ellisman,² and Palmer Taylor¹

Departments of ¹Pharmacology and ²Neurosciences and National Center For Microscopy and Imaging Research, University of California, San Diego, La Jolla, California 92093

The neuroligins are a family of postsynaptic transmembrane proteins that associate with presynaptic partners, the -neurexins. Neurexins and neuroligins play a critical role in initiating formation and differentiation of synaptic junctions. A recent study reported that a mutation of neuroligin-3 (NL3), an X-linked gene, was found in siblings with autistic spectrum disorder in which two affected brothers had a point mutation that substituted a Cys for Arg451. To characterize the mutation at the biochemical level, we analyzed expression and activity of the mutated protein. Mass spectrometry comparison of the disulfide bonding pattern between the native and the mutated proteins indicates the absence of aberrant disulfide bonding, suggesting that the secondary structure of the mutated protein is conserved. However, the mutation separately affects protein expression and activity. The Cys mutation causes defective neuroligin trafficking, leading to retention of the protein in the endoplasmic reticulum. This, in turn, decreases the delivery of NL3 to the cell surface. Also, the small fraction of protein that reaches the cell membrane lacks or has markedly diminished -neurexin-1 (NX1) binding activity. Other substitutions for Arg451 allow for normal cellular expression but diminished affinity for NX1. Our findings reveal a cellular phenotype and loss of function for a congenital mutation associated with autistic spectrum disorders.

Key words: neuroligin; neurexin; autism; cell adhesion proteins; thiol-retention; trafficking

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Received Feb 9, 2004; revised March 31, 2004; accepted April 13, 2004.

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