Abstract
Defects in mammalian glycinergic neurotransmission result in a complex motor disorder characterized by neonatal hypertonia and an exaggerated startle reflex, known as hyperekplexia (OMIM 149400). This affects newborn children and is characterized by noise or touch-induced seizures that result in muscle stiffness and breath-holding episodes. Although rare, this disorder can have serious consequences, including brain damage and/or sudden infant death. The primary cause of hyperekplexia is missense and non-sense mutations in the glycine receptor (GlyR) α1 subunit gene (GLRA1) on chromosome 5q33.1, although we have also discovered rare mutations in the genes encoding the GlyR β subunit (GLRB) and the GlyR clustering proteins gephyrin (GPNH) and collybistin (ARHGEF9). Recent studies of the Na+/Cl−-dependent glycine transporters GlyT1 and GlyT2 using mouse knockout models and human genetics have revealed that mutations in GlyT2 are a second major cause of hyperekplexia, while the phenotype of the GlyT1 knockout mouse resembles a devastating neurological disorder known as glycine encephalopathy (OMIM 605899). These findings highlight the importance of these transporters in regulating the levels of synaptic glycine.
Highlights
We have employed an alternative approach to the study of inhibitory synapses, integrating data from mouse models and proteomic studies to identify biologically plausible candidate genes for genetic analysis in human neurological disorders
This approach has resulted in the identification of mutations in the genes for the glycine receptor (GlyR) α1 and β subunits (Rees et al, 1994, 2001, 2002), gephyrin (Rees et al, 2003) and the RhoGEF collybistin (Harvey et al, 2004), all postsynaptic proteins found at inhibitory synapses (Figure 1)
Alignments of GlyT2 and leucine transporter (LeuT) revealed that mutations that disrupt glycine or Na+ binding to GlyT2 were predicted to form part of equivalent leucine or Na+ binding sites on LeuT (Figure 2). These results demonstrated that SLC6A5 was a major gene for hyperekplexia and defined the first neurological disorder linked to mutations in a Na+/Cl−-dependent transporter for a classical fast neurotransmitter
Summary
We have employed an alternative approach to the study of inhibitory synapses, integrating data from mouse models and proteomic studies to identify biologically plausible candidate genes for genetic analysis in human neurological disorders. It was of interest that Gomeza et al (2003b) reported that the phenotype of knockout mice for the presynaptic glycine transporter GlyT2 resembled human hyperekplexia.
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