Please cite this article in press as: A. Stepanyan, et al., The netrin G1 gene rs628117 polymorphism is associated with ischemic stroke, Neurosci. Lett. (2013), http://dx.doi.org/10.1016/j.neulet.2013.05.066 ARTICLE IN PRESS G Model NSL 29822 1–4 Neuroscience Letters xxx (2013) xxx–xxx Contents lists available at SciVerse ScienceDirect Neuroscience Letters jou rn al hom epage: www.elsevier.com/locate/neulet The netrin G1 gene rs628117 polymorphism is associated with ischemic stroke Ani Stepanyan, Roksana Zakharyan, Anna Boyajyan ∗ Q1 Institute of Molecular Biology, National Academy of Sciences of the Republic of Armenia (NAS RA), Armenia Q2 h i g h l i g h t s • The netrinG1 rs628117 polymorphism is associated with ischemic stroke. • Carriers of the rs628117*G minor allele are overrepresented in stroke patients. • The rs628117*G minor allele represents a risk factor for ischemic stroke. a r t i c l e i n f o Article history: Received 14 February 2013 Received in revised form 16 May 2013 Accepted 20 May 2013 Keywords: Ischemic stroke Netrin G1 Single nucleotide polymorphism a b s t r a c t Recent studies demonstrated that naturally occurring genetic alterations in synaptic plasticity-related Q3 genes may influence both stroke progression and poor functional recovery after stroke. Netrin G1 is an axonal protein involved in synaptic plasticity. In the present study, we evaluated the potential association of the netrin G1 gene rs628117 single nucleotide polymorphism with ischemic stroke in an Armenian population. In total, 127 patients with ischemic stroke and 128 healthy subjects (controls) were involved in this study. Genomic DNA samples of ischemic stroke patients and controls were genotyped for netrin G1 gene (NTNG1) rs628117 single nucleotide polymorphism using polymerase chain reaction with sequence- specific primers. Data were analyzed by Pearson’s  2 test. The results obtained implicated rs628117 single nucleotide polymorphism of NTNG1 in pathogenesis of ischemic stroke. In particular, it was shown that the NTNG1 rs628117*G minor allele is positively associated with ischemic stroke and the carriers of this allele were overrepresented in ischemic stroke patients compared with controls. Our finding nominates the minor G allele of the NTNG1 rs628117 single nucleotide polymorphism as a risk factor for ischemic stroke at least in Armenian population. © 2013 Published by Elsevier Ireland Ltd. 1. Introduction Recent studies demonstrated that naturally occurring genetic alterations in synaptic plasticity-related genes may influence both stroke progression [14,17,19,32] and poor functional recovery after stroke [7,30]. Netrin G1 is a member of the UNC-6/netrin family proteins that direct cell and axon migration during development. Netrin G1 is an axonal protein involved in synaptic plasticity. Unlike classi- cal secreted netrins, netrin G1 is bound to the plasma membrane through a glycosyl phosphatidylinositol anchor [23,24,34] and may regulate axonal and dendritic growth and guidance through bi- directional mechanisms [23]. Netrin G1 binds to specific ligand (NGL-1) [18,22], which is a membrane-bound post-synaptic protein ∗ Corresponding author at: 7 Hasratyan, 0014 Yerevan, Armenia. Tel.: +374 10281626; fax: +374 10282061. E-mail address: aboyajyan@sci.am (A. Boyajyan). containing an intracellular binding domain (PDZ-domain) thought to be important in affecting downstream signaling events, and a leucine-rich repeat extracellular domain that forms a horseshoe- shaped hook with which it binds to its pre-synaptic partner [3]. Netrin G1 together with NGL-1 promote neurite outgrowth, regu- late synapse formation and the balance between excitatory versus inhibitory inputs [18,22–24]. In particular, this protein promotes thalamocortical axon outgrowth [18], induces and maintains excit- atory synapse formation [22] and contributes to subdendritic segmentation in the hippocampus and cortex [25]. Furthermore, promising finding suggest that netrin G1 is also implicated in the immune response [2,15,16,31], which is a key element of the ischemic stroke (IS) progression [13]. This protein as a guidance cue might be involved in immune cell interactions and trafficking [31], and has an important role in the N-methyl- d-aspartate receptors activation [2], which triggers neuronal cell death in the brain by modulating inflammation [15]. In addition, it is proposed that netrin G1 may inhibit leukocyte chemotaxis in microglia [16]. 0304-3940/$ – see front matter © 2013 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.neulet.2013.05.066 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54