Disorder-associated mutations lead to functional inactivation of neuroligins
- 18 May 2004
- journal article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 13 (14), 1471-1477
- https://doi.org/10.1093/hmg/ddh158
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.Keywords
This publication has 38 references indexed in Scilit:
- Postnatal Neurodevelopmental Disorders: Meeting at the Synapse?Science, 2003
- AutismThe Lancet, 2003
- The Neurobiological Context of AutismMolecular Neurobiology, 2003
- Genetics of austim: complex aetiology for a heterogeneous disorderNature Reviews Genetics, 2001
- Autism Spectrum DisordersNeuron, 2000
- Decreased dendritic branching in frontal, motor and limbic cortex in Rett syndrome compared with trisomy 21.Journal of Neuropathology and Experimental Neurology, 1998
- Regional differences in synaptogenesis in human cerebral cortexJournal of Comparative Neurology, 1997
- Hippocampus in autism: a Golgi analysisActa Neuropathologica, 1995
- Autism as a strongly genetic disorder: evidence from a British twin studyPsychological Medicine, 1995
- INFANTILE AUTISM: A GENETIC STUDY OF 21 TWIN PAIRSJournal of Child Psychology and Psychiatry, 1977