RT Journal Article SR Electronic T1 Pathophysiological Mechanisms of Dominant and Recessive GLRA1 Mutations in Hyperekplexia JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 9612 OP 9620 DO 10.1523/JNEUROSCI.1763-10.2010 VO 30 IS 28 A1 Seo-Kyung Chung A1 Jean-François Vanbellinghen A1 Jonathan G. L. Mullins A1 Angela Robinson A1 Janina Hantke A1 Carrie L. Hammond A1 Daniel F. Gilbert A1 Michael Freilinger A1 Monique Ryan A1 Michael C. Kruer A1 Amira Masri A1 Candan Gurses A1 Colin Ferrie A1 Kirsten Harvey A1 Rita Shiang A1 John Christodoulou A1 Frederick Andermann A1 Eva Andermann A1 Rhys H. Thomas A1 Robert J. Harvey A1 Joseph W. Lynch A1 Mark I. Rees YR 2010 UL http://www.jneurosci.org/content/30/28/9612.abstract AB Hyperekplexia is a rare, but potentially fatal, neuromotor disorder characterized by exaggerated startle reflexes and hypertonia in response to sudden, unexpected auditory or tactile stimuli. This disorder is primarily caused by inherited mutations in the genes encoding the glycine receptor (GlyR) α1 subunit (GLRA1) and the presynaptic glycine transporter GlyT2 (SLC6A5). In this study, systematic DNA sequencing of GLRA1 in 88 new unrelated human hyperekplexia patients revealed 19 sequence variants in 30 index cases, of which 21 cases were inherited in recessive or compound heterozygote modes. This indicates that recessive hyperekplexia is far more prevalent than previous estimates. From the 19 GLRA1 sequence variants, we have investigated the functional effects of 11 novel and 2 recurrent mutations. The expression levels and functional properties of these hyperekplexia mutants were analyzed using a high-content imaging system and patch-clamp electrophysiology. When expressed in HEK293 cells, either as homomeric α1 or heteromeric α1β GlyRs, subcellular localization defects were the major mechanism underlying recessive mutations. However, mutants without trafficking defects typically showed alterations in the glycine sensitivity suggestive of disrupted receptor function. This study also reports the first hyperekplexia mutation associated with a GlyR leak conductance, suggesting tonic channel opening as a new mechanism in neuronal ligand-gated ion channels.