Abstract
Regulation of neuronal connectivity and synaptic communication are key to proper functioning of the brain. The Netrin-G subfamily and their cognate receptors are vertebrate-specific synaptic cell adhesion molecules with a role in synapse establishment and function, which seem to have co-evolved to contribute to higher brain functions. We identified a homozygous frameshift variant in NTNG2 (NM_032536.3: c.376dup), encoding Netrin-G2, in eight individuals from four families with global developmental delay, hypotonia, secondary microcephaly, and autistic features. Comparison of haplotypes established this as a founder variant. Previous studies showed that Ntng2-knockout mice have impaired visual, auditory, and motor coordination abilities required for demanding tasks, as well as possible spatial learning and memory deficits. Knockout of Ntng2 in a cellular model resulted in short neurites, and knockout of its trans-synaptic partner Ngl2/Lrrc4 in mice revealed autistic-like behavior and reduced NMDAR synaptic plasticity. The Ngl2/Lrrc4-knockout mouse phenotype was rescued by NMDAR activation, suggesting a mechanistic link to autism spectrum disorder. We thus propose NTNG2 as a candidate disease gene and provide further support for ...Continue Reading
References
Jan 24, 2002·Mechanisms of Development·Toshiaki NakashibaShigeyoshi Itohara
Mar 22, 2002·Molecular and Cellular Neurosciences·Yong YinJoshua R Sanes
Feb 12, 2005·Biological Psychiatry·Mika Aoki-SuzukiTakeo Yoshikawa
May 5, 2005·European Journal of Human Genetics : EJHG·Isabella BorgVera M Kalscheuer
May 18, 2007·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Sharon L Eastwood, Paul J Harrison
Sep 6, 2007·Proceedings of the National Academy of Sciences of the United States of America·Sachiko Nishimura-AkiyoshiShigeyoshi Itohara
Apr 4, 2008·Neuroscience Letters·T OhtsukiT Arinami
May 27, 2009·Molecular and Cellular Neurosciences·Jooyeon WooEunjoon Kim
May 12, 2011·Development·Karen Lai Wing SunTimothy E Kennedy
Sep 29, 2011·The EMBO Journal·Elena SeiradakeEdith Yvonne Jones
Aug 28, 2012·Nature Cell Biology·Sara RicciardiVania Broccoli
Jul 19, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Florentina SotoDaniel Kerschensteiner
Aug 19, 2014·Trends in Neurosciences·Joris de Wit, Anirvan Ghosh
Nov 21, 2014·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Hiroshi MatsukawaShigeyoshi Itohara
May 8, 2015·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Gang XuMinghua Wu
Aug 21, 2015·Nature Reviews. Neuroscience·Thomas Bourgeron
Jan 10, 2016·Molecular Brain·Qi ZhangShigeyoshi Itohara
Jul 17, 2016·Journal of Molecular Neuroscience : MN·Gengze WeiJun Xu
Feb 23, 2017·Human Genome Variation·Noriko SanguToshiyuki Yamamoto
Apr 9, 2017·Current Opinion in Neurobiology·Seil JangEunjoon Kim
Jun 28, 2018·Cell Reports·Seung Min UmEunjoon Kim