AUTHOR=Harvey Robert J., Carta Eloisa , Pearce Brian R., Chung Seo-Kyung , Supplisson Stéphane , Rees Mark I., Harvey Kirsten 

TITLE=A critical role for glycine transporters in hyperexcitability disorders

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=Volume 1 - 2008

YEAR=2008

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/neuro.02.001.2008

DOI=10.3389/neuro.02.001.2008

ISSN=1662-5099

ABSTRACT=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) &#945;1 subunit gene <I>(GLRA1)</I> on chromosome 5q33.1, although we have also discovered  rare mutations in the genes encoding the GlyR &#946; 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.