ArticleThe Journal of biological chemistry2016
Investigating the Mechanism by Which Gain-of-function Mutations to the α1 Glycine Receptor Cause Hyperekplexia.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 18 citations in OpenAlex.
- Milestone Review: Unlocking the Proteomics of Glycine Receptor Complexes.Journal of neurochemistry · 2025Review
- The emerging role of glycine receptor α2 subunit defects in neurodevelopmental disorders.Frontiers in molecular neuroscience · 2025Review
- The implications of hyperekplexia on children's quality of life: a report on two cases.Revista paulista de pediatria : orgao oficial da Sociedade de Pediatria de Sao Paulo · 2025Article
- Startle Disease: New Molecular Insights into an Old Neurological Disorder.The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry · 2023Review
- Loss, Gain and Altered Function of GlyR α2 Subunit Mutations in Neurodevelopmental Disorders.Frontiers in molecular neuroscience · 2022Article
- Advances in hyperekplexia and other startle syndromes.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2021Review
- The startle disease mutation α1S270T predicts shortening of glycinergic synaptic currents.The Journal of physiology · 2020Article
- Anxiety and Startle Phenotypes inFrontiers in molecular neuroscience · 2020Article
- The role of tonic glycinergic conductance in cerebellar granule cell signalling and the effect of gain-of-function mutation.The Journal of physiology · 2019Article
- Impaired Glycine Receptor Trafficking in Neurological Diseases.Frontiers in molecular neuroscience · 2018Review
- Glycine is able to induce both a motility speed in- and decrease during zebrafish neuronal migration.Communicative & integrative biology · 2018Article
- Structure/Function Studies of the α4 Subunit Reveal Evolutionary Loss of a GlyR Subtype Involved in Startle and Escape Responses.Frontiers in molecular neuroscience · 2018Article
- Structure-Function Analysis of the GlyR α2 Subunit Autism Mutation p.R323L Reveals a Gain-of-Function.Frontiers in molecular neuroscience · 2017Article
- The Free Zinc Concentration in the Synaptic Cleft of Artificial Glycinergic Synapses Rises to At least 1 μM.Frontiers in molecular neuroscience · 2016Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hyperekplexia is a rare human neuromotor disorder caused by mutations that impair the efficacy of glycinergic inhibitory neurotransmission. Loss-of-function mutations in the GLRA1 or GLRB genes, which encode the α1 and β glycine receptor (GlyR) subunits, are the major cause. Paradoxically, gain-of-function GLRA1 mutations also cause hyperekplexia, although the mechanism is unknown. Here we identify two new gain-of-function mutations (I43F and W170S) and characterize these along with known gain-of-function mutations (Q226E, V280M, and R414H) to identify how they cause hyperekplexia. Using artificial synapses, we show that all mutations prolong the decay of inhibitory postsynaptic currents (IPSCs) and induce spontaneous GlyR activation. As these effects may deplete the chloride electrochemical gradient, hyperekplexia could potentially result from reduced glycinergic inhibitory efficacy. However, we consider this unlikely as the depleted chloride gradient should also lead to pain sensitization and to a hyperekplexia phenotype that correlates with mutation severity, neither of which is observed in patients with GLRA1 hyperekplexia mutations. We also rule out small increases in IPSC decay times (as caused by W170S and R414H) as a possible mechanism given that the clinically important drug, tropisetron, significantly increases glycinergic IPSC decay times without causing motor side effects. A recent study on cultured spinal neurons concluded that an elevated intracellular chloride concentration late during development ablates α1β glycinergic synapses but spares GABAergic synapses. As this mechanism satisfies all our considerations, we propose it is primarily responsible for the hyperekplexia phenotype.
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