| Summary: | Defects in mammalian glycinergic neurotransmission result in a complex motor disorder characterized by neonatal hypertonia and an exaggerated startle refl ex, 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 nonsense mutations in the glycine receptor (GlyR) α1 subunit gene <I>(GLRA1)</I> on chromosome 5q33.1, although we have also discovered rare mutations in the genes encoding the GlyR β subunit <I>(GLRB)</I> and the GlyR clustering proteins gephyrin <I>(GPNH)</I> and collybistin <I>(ARHGEF9)</I>. Recent studies of the Na<sup>+</sup> /Cl<sup>-</sup>-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.
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