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: Ben Chih, Shehla Khan Afridi, Lorraine Clark, Peter Scheiffele
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 13 Issue 14 Pg. 1471-7 (Jul 15 2004) ISSN: 0964-6906 [Print] England
• PMID: 15150161 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Cell Adhesion Molecules, Neuronal
• Membrane Proteins
• NLGN4X protein, human
• Nerve Tissue Proteins
• neuroligin 3
• Aspartic Acid
• Arginine

Topics

• Animals
• Arginine (genetics)
• Aspartic Acid (genetics)
• Autistic Disorder (genetics)
• COS Cells
• Carrier Proteins (genetics, metabolism)
• Cell Adhesion Molecules, Neuronal
• Chlorocebus aethiops
• Genetic Predisposition to Disease
• Hippocampus (metabolism)
• Humans
• Intellectual Disability (genetics)
• Membrane Proteins (genetics, metabolism)
• Mutation, Missense
• Nerve Tissue Proteins (genetics, metabolism)
• Neurons (metabolism)
• Point Mutation
• Protein Transport