Pathophysiological Mechanisms of Dominant and Recessive GLRA1 Mutations in Hyperekplexia

• DOI: 10.1523/jneurosci.1763-10.2010
• Publication Date: 2013-07-08T17:41:44Z
• Authors: S.-K. Chung; J.-F. Vanbellinghen; J. G. L. Mullins; A. Robinson; J. Hantke; C. L. Hammond; D. F. Gilbert; M. Freilinger; M. Ryan; M. C. Kruer; A. Masri; C. Gurses; C. Ferrie; K. Harvey; R. Shiang; J. Christodoulou; F. Andermann; E. Andermann; R. H. Thomas; R. J. Harvey; J. W. Lynch; M. I. Rees
• Keywords: Homomeric; Compound heterozygosity; HEK 293 cells; Hypertonia

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 primarily caused inherited mutations the genes encoding glycine receptor (GlyR) alpha1 subunit (GLRA1) presynaptic transporter GlyT2 (SLC6A5). In this study, systematic DNA sequencing of GLRA1 88 new unrelated human hyperekplexia patients revealed 19 sequence variants 30 index cases, which 21 cases were recessive compound heterozygote modes. indicates that far more prevalent than previous estimates. From variants, we have investigated functional effects 11 novel 2 recurrent mutations. The expression levels properties these mutants analyzed using high-content imaging system patch-clamp electrophysiology. When expressed HEK293 cells, either as homomeric heteromeric alpha1beta GlyRs, subcellular localization defects major mechanism underlying However, without trafficking typically showed alterations sensitivity suggestive disrupted function. study also reports first mutation associated with GlyR leak conductance, suggesting tonic channel opening neuronal ligand-gated ion channels.