Human Molecular Genetics Advance Access originally published online on May 18, 2004
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. Mason The Development of Developmental Neuroscience J. Neurosci., October 14, 2009; 29(41): 12735 - 12747. [Full Text] [PDF]
|
|
|
|
 |
|
 N. Giagtzoglou, C. V. Ly, and H. J. Bellen Cell Adhesion, the Backbone of the Synapse: "Vertebrate" and "Invertebrate" Perspectives Cold Spring Harb Perspect Biol, October 1, 2009; 1(4): a003079 - a003079. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Zhang, J. M. Milunsky, S. Newton, J. Ko, G. Zhao, T. A. Maher, H. Tager-Flusberg, M. F. Bolliger, A. S. Carter, A. A. Boucard, et al. A Neuroligin-4 Missense Mutation Associated with Autism Impairs Neuroligin-4 Folding and Endoplasmic Reticulum Export J. Neurosci., September 2, 2009; 29(35): 10843 - 10854. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Pescini Gobert, L. Joubert, M.-L. Curchod, C. Salvat, I. Foucault, C. Jorand-Lebrun, M. Lamarine, H. Peixoto, C. Vignaud, C. Fremaux, et al. Convergent Functional Genomics of Oligodendrocyte Differentiation Identifies Multiple Autoinhibitory Signaling Circuits Mol. Cell. Biol., March 15, 2009; 29(6): 1538 - 1553. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C Lintas and A M Persico Autistic phenotypes and genetic testing: state-of-the-art for the clinical geneticist J. Med. Genet., January 1, 2009; 46(1): 1 - 8. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. K. Seabold, P. Y. Wang, K. Chang, C.-Y. Wang, Y.-X. Wang, R. S. Petralia, and R. J. Wenthold The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes J. Biol. Chem., March 28, 2008; 283(13): 8395 - 8405. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Koehnke, X. Jin, E. C. Budreck, S. Posy, P. Scheiffele, B. Honig, and L. Shapiro Crystal structure of the extracellular cholinesterase-like domain from neuroligin-2 PNAS, February 12, 2008; 105(6): 1873 - 1878. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Tabuchi, J. Blundell, M. R. Etherton, R. E. Hammer, X. Liu, C. M. Powell, and T. C. Sudhof A Neuroligin-3 Mutation Implicated in Autism Increases Inhibitory Synaptic Transmission in Mice Science, October 5, 2007; 318(5847): 71 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Bourgeron The Possible Interplay of Synaptic and Clock Genes in Autism Spectrum Disorders Cold Spring Harb Symp Quant Biol, January 1, 2007; 72(0): 645 - 654. [Abstract] [PDF]
|
|
|
|
 |
|
 E. J. Marco and D. H. Skuse Autism-lessons from the X chromosome Soc Cogn Affect Neurosci, December 1, 2006; 1(3): 183 - 193. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z Talebizadeh, D Y Lam, M F Theodoro, D C Bittel, G H Lushington, and M G Butler Novel splice isoforms for NLGN3 and NLGN4 with possible implications in autism. J. Med. Genet., May 1, 2006; 43(5): e21 - e21. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. De Jaco, D. Comoletti, Z. Kovarik, G. Gaietta, Z. Radic, O. Lockridge, M. H. Ellisman, and P. Taylor A Mutation Linked with Autism Reveals a Common Mechanism of Endoplasmic Reticulum Retention for the {alpha},beta-Hydrolase Fold Protein Family J. Biol. Chem., April 7, 2006; 281(14): 9667 - 9676. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Chubykin, X. Liu, D. Comoletti, I. Tsigelny, P. Taylor, and T. C. Sudhof Dissection of Synapse Induction by Neuroligins: EFFECT OF A NEUROLIGIN MUTATION ASSOCIATED WITH AUTISM J. Biol. Chem., June 10, 2005; 280(23): 22365 - 22374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Chih, H. Engelman, and P. Scheiffele Control of Excitatory and Inhibitory Synapse Formation by Neuroligins Science, February 25, 2005; 307(5713): 1324 - 1328. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Washbourne, A. Dityatev, P. Scheiffele, T. Biederer, J. A. Weiner, K. S. Christopherson, and A. El-Husseini Cell Adhesion Molecules in Synapse Formation J. Neurosci., October 20, 2004; 24(42): 9244 - 9249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Prange, T. P. Wong, K. Gerrow, Y. T. Wang, and A. El-Husseini A balance between excitatory and inhibitory synapses is controlled by PSD-95 and neuroligin PNAS, September 21, 2004; 101(38): 13915 - 13920. [Abstract] [Full Text] [PDF]
|
|