title: Disorder-associated mutations lead to functional inactivation of neuroligins.
abstract: 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.
authors.affiliation: Department of Physiology and Cellular Biophysics, Center for Neurobiology and Behavior, Columbia University, New York, NY 10032, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Chih
authors.forename: Shehla Khan
authors.initials: SK
authors.lastname: Afridi
authors.forename: Lorraine
authors.initials: L
authors.lastname: Clark
authors.forename: Peter
authors.initials: P
authors.lastname: Scheiffele
mesh_terms: D000818:Animals; D001120:Arginine / Q000235:genetics; D001224:Aspartic Acid / Q000235:genetics; D001321:Autistic Disorder / Q000235:genetics*; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal; D002522:Chlorocebus aethiops; D020022:Genetic Predisposition to Disease; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D017354:Point Mutation; D021381:Protein Transport
chemical_list: D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; D008565:Membrane Proteins; C430845:NLGN4X protein, human; D009419:Nerve Tissue Proteins; C098004:neuroligin 3; D001224:Aspartic Acid; D001120:Arginine