Human Molecular Genetics Advance Access originally published online on May 18, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 14 1471-1477
DOI: 10.1093/hmg/ddh158
Human Molecular Genetics, Vol. 13, No. 14 © Oxford University Press 2004; all rights reserved
Disorder-associated mutations lead to functional inactivation of neuroligins
1Department of Physiology and Cellular Biophysics, Center for Neurobiology and Behavior and 2Taub Institute, Department of Pathology, Columbia University, New York, NY 10032, USA
Received March 15, 2004; Accepted May 11, 2004
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 at arginine 451 and a nonsense mutation at aspartate 396 of neuroligin-3 and -4 (NL3 and NL4), respectively, result in intracellular retention of the mutant proteins. Over-expression of wild-type NL3 and NL4 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 neuro-developmental defects in autism-spectrum disorders and mental retardation since they impair the function of a synaptic cell adhesion molecule.
* To whom correspondence should be addressed: Tel: +1 2123050204; Fax: +1 2123055775; Email: ps2018{at}columbia.edu
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