Table 2.
Summary of genes and proteins linked to synaptic function that are implicated, either directly through mutation or indirectly as secondary effects, in neurodevelopmental and associated disorders.
| Gene human mouse | Encoded protein | Localization and/or function | Human populations | Mouse models |
|---|---|---|---|---|
| GABRA1 Gabra1 | α1 subunit of the GABAA receptor | Enriched at synaptic sites on dendrites and soma, relatively rapid decay | Epilepsy (Cossette et al., 2002) Dravet Syndrome (Carvill et al., 2014) | |
| GABRA2 Gabra2 | α2 subunit of the GABAA receptor | Enriched at synaptic sites on AIS, and early in development, relatively slow decay | Dravet Syndrome (Carvill et al., 2014) | Dravet Syndrome (Hawkins et al., 2016) |
| GABRA3 Gabra3 | α3 subunit of the GABAA receptor | Found in phasic receptors predominantly on the dendrites, high sensitivity to GABA | Epilepsy (Niturad et al., 2017) | Epilepsy (Niturad et al., 2017) |
| GABRA4 Gabra4 | α4 subunit of the GABAA receptor | Extrasynaptic localization (tonic), diazepam insensitive, high sensitivity to GABA | ASD (Ma et al., 2005; Sesarini et al., 2015) | |
| GABRA5 Gabra5 | α5 subunit of the GABAA receptor | Extrasynaptic localization (tonic), diazepam insensitive, high sensitivity to GABA | Angelman Syndrome (Pelc et al., 2008) ASD (Dup15q) (Park and Bolton, 2001; Kwasnicka-Crawford et al., 2007; Depienne et al., 2009) | Epilepsy (Vien et al., 2015) |
| GABRA6 Gabra6 | α6 subunit of the GABAA receptor | Extrasynaptic localization (tonic), diazepam insensitive, high sensitivity to GABA | Epilepsy (Hernandez et al., 2011) | |
| GABRB1 Gabra1 | β1 subunit of the GABAA receptor | Histamine, benzodiazepine, and anesthetic sensitive | ASD (Collins et al., 2006) | |
| GABRB2 Gabrb2 | β2 subunit of the GABAA receptor | Histamine, benzodiazepine, and anesthetic sensitive | Epilepsy (Srivastava et al., 2014) Schizophrenia (Lo et al., 2007) | |
| GABRB3 Gabrb3 | β3 subunit of the GABAA receptor | ASD (Dup15q) (Park and Bolton, 2001; Kwasnicka-Crawford et al., 2007; Depienne et al., 2009) Angelman Syndrome (Tanaka et al., 2012) Epilepsy (Tanaka et al., 2012) | Angelman Syndrome (Tanaka et al., 2012) Epilepsy (Tanaka et al., 2012; Vien et al., 2015) | |
| GABRG2 Gabrg2 | γ2 subunit of the GABAA receptor | Most common subunit in synaptic receptors, relatively large channel conductance | Epilepsy (Baulac et al., 2001; Wallace et al., 2001) Dravet Syndrome (Huang et al., 2012) | |
| GABRG3 Gabrg3 | γ3 subunit of the GABAA receptor | ASD (Dup15q) (Park and Bolton, 2001; Kwasnicka-Crawford et al., 2007; Depienne et al., 2009) Angelman Syndrome (Pelc et al., 2008) | ||
| GABRD Gabrd | δ subunit of the GABAA receptor | Extrasynaptic localization (tonic), diazepam insensitive, high sensitivity to GABA | Epilepsy (Macdonald et al., 2012) | Epilepsy (Macdonald et al., 2012) |
| GPHN Gphn | Gephyrin | Scaffolding protein of inhibitory synapses, protein–cytoskeleton interaction | ASD (Chen et al., 2014)-rare | |
| ARHGEF9 Arhgef9 | Rho guanine nucleotide exchange factor 9/collybistin | Scaffolding protein of inhibitory synapses | ASD (Chen et al., 2014)-rare Hyperekplexia (Tijssen and Rees, 1993; Kalscheuer et al., 2009; Alber et al., 2017) Intellectual disability (Kalscheuer et al., 2009; Long et al., 2015) | Hyperekplexia (Tijssen and Rees, 1993; Harvey et al., 2004) |
| NRXN1 Nrxn1 | Neurexin1 | Cell surface proteins involved in cell–cell interactions, export of secretory granules and modulation of signaling | ASD (Pizzarelli and Cherubini, 2011; Chen et al., 2014) | ASD (Pizzarelli and Cherubini, 2011; Grayton et al., 2013) |
| NRXN2 Nrxn2 | Neurexin2 | |||
| NRXN3 Nrxn3 | Neurexin3 | |||
| CNTNAP2 Cntnap2 | Contactin associated protein-like 2 CSPR2 | Role player in formation of domains for salutatory conduction of nervous impulses, part of neurexin family | ASD (Jacob, 2016; Rodenas-Cuadrado et al., 2016) Epilepsy (Jacob, 2016) | ASD (Peñagarikano et al., 2011) |
| NLGN1 Nlgn1 | Neuroligin-1 | Cell surface protein with role in synapse function via interaction with neurexin, localized at excitatory synapses | ASD (Pizzarelli and Cherubini, 2011; Chen et al., 2014) | ASD (Dahlhaus et al., 2010) Rett Syndrome (Pizzarelli and Cherubini, 2011) Fragile-X (Dahlhaus and El-Husseini, 2010) |
| NLGN2 Nlgn2 | Neuroligin-2 | Scaffolding protein that interacts with neurexins to aid in cell–cell interaction, localized at inhibitory synapses | ASD (Hines et al., 2008) | |
| NLGN3 Nlgn3 | Neuroligin-3 | Cell surface protein with role in synapse function via interaction with neurexin, localized at excitatory and inhibitory synapses | ASD (Tabuchi et al., 2007; Jaramillo et al., 2014) | |
| NLGN4 Nlgn4 | Neuroligin-4 | Cell surface protein involved in cell–cell interactions, localized at inhibitory synapses | ASD (Jamain et al., 2008) | |
| CNTN Cntn | Contactins | Mediators of cell surface interactions during nervous system development | ASD (Bakkaloglu et al., 2008) | ASD (Banerjee et al., 2014) |
| SHANK2 Shank2 | SH3 and multiple ankyrin repeat domains protein 2 | Scaffolding protein of inhibitory synapses | ASD (Schmeisser et al., 2012; Banerjee et al., 2014) | |
| SHANK3 Shank3 | SH3 and multiple ankyrin repeat domains protein 3 | ASD (Durand et al., 2007) | ASD (Banerjee et al., 2014; McGee et al., 2014) | |
| MECP2 Mecp2 | Methyl-CpG-binding protein 2 | Chromosomal protein that binds to DNA that has been methylated | Rett Syndrome (Kozinetz et al., 1993; Amir et al., 1999; Banerjee et al., 2014) ASD (Tanaka et al., 2012) | Rett Syndrome (Chao et al., 2007; Medrihan et al., 2008) |
| UBE3A Ube3a | Ubiquitin-protein ligase E3A | Accepts ubiquitin from E2 and transfers to substrate | Angelman Syndrome (Jiang et al., 1998; Pelc et al., 2008) Epilepsy (Jiang et al., 1998) | |