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Disorder-associated mutations lead to functional inactivation of neuroligins
Journal
Human molecular genetics
Volume
13
Number
14
Pages / Article-Number
1471-7
Keywords
Animals; Arginine/genetics; Aspartic Acid/genetics; Autistic Disorder/*genetics; COS Cells; Carrier Proteins/*genetics/metabolism; Cercopithecus aethiops; Genetic Predisposition to Disease; Hippocampus/metabolism; Humans; Membrane Proteins/*genetics/metabolism; Mental Retardation/*genetics; Mutation; Missense; Nerve Tissue Proteins/*genetics/metabolism; Neurons/*metabolism; Point Mutation; Protein Transport
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.
