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Molecular genetics of glycinergic synapses
Defects in human glycinergic neurotransmission result in startle disease or hyperekplexia. This neurological disorder affects newborn children and is characterised by noise- or touch-induced seizures, which result in muscle stiffness and neonatal apnoea episodes. Although rare, this disorder can have serious consequences, including brain damage and/or sudden infant death. Startle disease is caused by defects in three genes encoding proteins involved in inhibitory glycinergic transmission - postsynaptic glycine receptor (GlyR) α1 and β subunits and a presynaptic Na+/Cl--dependent glycine transporter (GlyT2). For the GlyR α1 subunit gene, recessive mutations in this gene are common, causing subcellular localisation defects, alterations in the sensitivity to glycine or tonic ion-channel opening (Chung et al 2010, J Neurosci 30: 9612-9620). For GlyT2, we have uncovered new pathogenic mechanisms, including splice-site mutations and missense mutations affecting residues implicated in Cl- binding, conformational changes mediated by extracellular loop 4 and cation-π interactions (Carta et al 2012, J Biol Chem 287:28975-28985; Giménez et al 2012, J Biol Chem 287:28986-29002). Lastly, we characterised new mutations in the GlyR β subunit gene, revealing new pathogenic mechanisms including tonic ion-channel opening and defects in transmembrane stacking (Chung et al 2013, Hum Mol Genet 22:927-940; James et al 2013, Neurobiol Dis 52:137-149). We have also uncovered GlyT2 defects in congenital muscular dystonia type 2 in Belgian Blue cattle (Charlier et al 2008, Nat Genet 40:449-454) and in Irish Wolfhounds (Gill et al 2011, Neurobiol Dis 43:184-189). Future research aims to: i) Use genetic screening, functional assays and molecular modelling to characterise mutations in known hyperekplexia disease genes in humans and animals; ii) use array CGH, whole-exome sequencing and proteomics to uncover new causes of hyperekplexia in individuals that do not have mutations in known genes. Key collaborators include: Joe Lynch (University of Queensland, Australia), Mark Rees (ILS Swansea, Wales), Diane Shelton (University of California, San Diego, USA), Maya Topf (Birkbeck), August Smit (VU Amsterdam, The Netherlands).
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