The impact of human hyperekplexia mutations on glycine receptor structure and function

Abstract

Hyperekplexia is a rare neurological disorder characterized by neonatal hypertonia, exaggerated startle responses to unexpected stimuli and a variable incidence of apnoea, intellectual disability and delays in speech acquisition. The majority of motor defects are successfully treated by clonazepam. Hyperekplexia is caused by hereditary mutations that disrupt the functioning of inhibitory glycinergic synapses in neuromotor pathways of the spinal cord and brainstem. The human glycine receptor α1 and β subunits, which predominate at these synapses, are the major targets of mutations. International genetic screening programs, that together have analysed several hundred probands, have recently generated a clear picture of genotype-phenotype correlations and the prevalence of different categories of hyperekplexia mutations. Focusing largely on this new information, this review seeks to summarise the effects of mutations on glycine receptor structure and function and how these functional alterations lead to hyperekplexia.

Figure 1

Schematic of a hyperekplexia patient illustrating the sequence of movements during a startle reflex. Numbers represent elapsed time in ms. Reproduced with permission from Elsevier [2].

Figure 2

pLGIC structure and the locations of hGlyR hyperekplexia mutations. The top panel shows the pentameric structure of the C. elegans α glutamate-gated chloride channel receptor (PDB 3RIF [31]) viewed from within the membrane (A) and from the presynaptic terminal (B). One subunit is coloured light grey. Panels C-F show a single pLGIC subunit with the locations of dominant and recessive mutations in the α1 and β hGlyR subunits coloured in green (missense), red (nonsense) or black (deletions). TM2 is coloured dark grey.

Figure 3

Proposed mechanism by which Q226E induces spontaneous activation. The TM1 and TM2 helices are coloured green and red, respectively, and are located in adjacent subunits. A. In the wild type (WT) α1 hGlyR, glycine induces activation by tilting the top of TM2 away from the pore axis towards TM1, where the open state is weakly stabilized by an H-bond between Q226 and R271. Hyperekplexia mutations at R271 are likely to disrupt this bond, thus destabilising the open state. B. In the Q226E mutant α1 hGlyR, a stable open state in the absence of glycine is induced via the formation of a strong electrostatic bond between Q226E and R271.