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=1

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=<p>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 (<abbrev>GlyR</abbrev>) α1 subunit gene (<italic>GLRA1</italic>) on chromosome 5q33.1, although we have also discovered rare mutations in the genes encoding the <abbrev>GlyR</abbrev> β subunit (<italic><abbrev>GLRB</abbrev></italic>) and the <abbrev>GlyR</abbrev> clustering proteins gephyrin (<italic>GPNH</italic>) and collybistin (<italic>ARHGEF9</italic>). Recent studies of the Na<sup>+</sup>/Cl<sup>−</sup>-dependent glycine transporters <abbrev>GlyT1</abbrev> and <abbrev>GlyT2</abbrev> using mouse knockout models and human genetics have revealed that mutations in <abbrev>GlyT2</abbrev> are a second major cause of hyperekplexia, while the phenotype of the <abbrev>GlyT1</abbrev> 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.</p>