Human Molecular Genetics Advance Access published online on May 18, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh158
© 2004 by Oxford University Press
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1 Department of Physiology and Cellular Biophysics, Center for Neurobiology and Behavior, Columbia University, New York, NY 10032, USA
* To whom correspondence should be addressed. E-mail: ps2018{at}columbia.edu.
Autism is a neuro-developmental syndrome that affects 0.1-0.5% of the population. It has been proposed that alterations in neuronal circuitry and/or neuronal signaling are responsible for the behavioral and cognitive aberrations in autism patients. However, the cellular basis of such alterations is unknown. Recently, point mutations in a family of neuronal cell adhesion molecules called neuroligins have been linked to autism-spectrum disorders and mental retardation. We investigated the consequences of these disease-associated mutations on neuroligin function. We demonstrate that the point mutation in arginine 451 and a nonsense mutation at aspartate 396 of neuroligin-3 and -4, respectively, result in intracellular retention of the mutant proteins. Over-expression of wild-type neuroligin-3 and -4 proteins in hippocampal neurons stimulates the formation of presynaptic terminals whereas the disease-associated mutations result in a loss of this synaptic function. Our findings suggest that the previously identified mutations in neuroligin genes are likely to be relevant for the neurodevelopmental defects in autism-spectrum disorders and mental retardation since they impair the function of a synaptic cell adhesion molecule.
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Disorder-associated mutations lead to functional inactivation of neuroligins
2 Taub Institute, Department of Pathology, Columbia University, New York, NY 10032, USA
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