Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0234166 (Hyperekplexia)
 84 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperekplexia (startle disease) results from mutations in the glycine receptor chloride channel that disrupt inhibitory synaptic transmission. The Q266H missense mutation is the only hyperekplexia mutation located in the transmembrane domains of the receptor. Using recombinant expression and patch-clamping techniques, we have investigated the functional properties of this mutation. The ability of glycine and taurine to open the channel was reduced in the mutated channel, as shown by a 6-fold shift in the concentration-response curve for both agonists. This was not accompanied by similar changes in agonist displacement of strychnine binding, suggesting that the mutation affects functions subsequent to ligand binding. Taurine was also converted to a weak partial agonist and antagonized the actions of glycine, consistent with changes in its channel gating efficacy. Because the Q266H mutation is within the pore-forming second transmembrane domain, we tested for a direct interaction with permeating ions. No change in either the cation/anion selectivity ratio or in single channel conductance levels was observed. No differential effects of Zn++, pH, and diethylpyrocarbonate were observed, implying that the histidine side chain is not exposed to the channel lumen. Single-channel recordings revealed a significant reduction in open times in the mutant receptors, at both high and low agonist concentrations, consistent with the open state of the channel being less stable. This study demonstrates that residues within the second transmembrane domain of ligand-gated ion channel receptors, even those whose side chains do not directly interact with permeating ions, can affect the kinetics of channel gating.
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PMID:The startle disease mutation Q266H, in the second transmembrane domain of the human glycine receptor, impairs channel gating. 992 32

Hyperekplexia is primarily an autosomal dominant disease characterized by exaggerated startle reflex and neonatal hypertonia. It can be associated with, if untreated, sudden infant death from apnea or aspiration pneumonia and serious injuries and loss of ambulation from frequent falls. Different mutations in the alpha1 subunit of inhibitory glycine receptor (GLRA1) gene have been identified in many affected families. The most common mutation is Arg271 reported in at least 12 independent families. These mutations uncouple the ligand binding and chloride channel function of inhibitory glycine receptor and result in increased excitability in pontomedullary reticular neurons and abnormal spinal reciprocal inhibition. Three mouse models from spontaneous mutations in GLRA1 and beta subunit of inhibitory glycine receptor (GLRB) genes and two transgenic mouse models are valuable for the study of the pathophysiology and the genotype-phenotype correlation of the disease. The disease caused by mutation in GLRB in mice supports the notion that human hyperekplexia with no detectable mutations in GLRA1 may harbor mutations in GLRB. Clonazepam, a gamma aminobutyric acid (GABA) receptor agonist, is highly effective and is the drug of choice. It enhances the GABA-gated chloride channel function and presumably compensates for the defective glycine-gated chloride channel in hyperekplexia. Recognition of the disease will lead to appropriate treatment and genetic counseling.
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PMID:Hyperekplexia: a treatable neurogenetic disease. 1242 12