Trial reportThe Journal of biological chemistry2013
New hyperekplexia mutations provide insight into glycine receptor assembly, trafficking, and activation mechanisms.
Trial report in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
35 citing papers in PubMed, 43 citations in OpenAlex.
- Mechanism of human α3β GlyR regulation by intracellular M3/M4 loop phosphorylation and 2,6-di-tert-butylphenol interaction.Nature communications · 2025Article
- 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
- Exploring the Activation Process of the Glycine Receptor.Journal of the American Chemical Society · 2024Article
- Allosteric Cholesterol Site in Glycine Receptors Characterized through Molecular Simulations.The journal of physical chemistry. B · 2024Article
- Article
- Illumination of a progressive allosteric mechanism mediating the glycine receptor activation.Nature communications · 2023Article
- Expression of Mutant Glycine Receptors inMembranes · 2022Article
- Exploring the Conformational Impact of Glycine Receptor TM1-2 Mutations Through Coarse-Grained Analysis and Atomistic Simulations.Frontiers in molecular biosciences · 2022Article
- 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
- Novel Functional Properties of Missense Mutations in the Glycine Receptor β Subunit in Startle Disease.Frontiers in molecular neuroscience · 2021Article
- A Novel Glycine Receptor Variant with Startle Disease Affects Syndapin I and Glycinergic Inhibition.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- Excessive Startle with NovelJournal of clinical neurology (Seoul, Korea) · 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
- Clinical features and genetic analysis of two siblings with startle disease in an Italian family: a case report.BMC medical genetics · 2019Article
- A novel nonsense autosomal dominant mutation in the GLRA1 gene causing hyperekplexia.Journal of neural transmission (Vienna, Austria : 1996) · 2018Article
- A Missense Mutation A384P Associated with Human Hyperekplexia Reveals a Desensitization Site of Glycine Receptors.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2018Article
- Impaired Glycine Receptor Trafficking in Neurological Diseases.Frontiers in molecular neuroscience · 2018Review
- 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
Corrections and comments
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Authors and funding
35 authors at 20 institutions in 14 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hyperekplexia is a syndrome of readily provoked startle responses, alongside episodic and generalized hypertonia, that presents within the first month of life. Inhibitory glycine receptors are pentameric ligand-gated ion channels with a definitive and clinically well stratified linkage to hyperekplexia. Most hyperekplexia cases are caused by mutations in the α1 subunit of the human glycine receptor (hGlyR) gene (GLRA1). Here we analyzed 68 new unrelated hyperekplexia probands for GLRA1 mutations and identified 19 mutations, of which 9 were novel. Electrophysiological analysis demonstrated that the dominant mutations p.Q226E, p.V280M, and p.R414H induced spontaneous channel activity, indicating that this is a recurring mechanism in hGlyR pathophysiology. p.Q226E, at the top of TM1, most likely induced tonic activation via an enhanced electrostatic attraction to p.R271 at the top of TM2, suggesting a structural mechanism for channel activation. Receptors incorporating p.P230S (which is heterozygous with p.R65W) desensitized much faster than wild type receptors and represent a new TM1 site capable of modulating desensitization. The recessive mutations p.R72C, p.R218W, p.L291P, p.D388A, and p.E375X precluded cell surface expression unless co-expressed with α1 wild type subunits. The recessive p.E375X mutation resulted in subunit truncation upstream of the TM4 domain. Surprisingly, on the basis of three independent assays, we were able to infer that p.E375X truncated subunits are incorporated into functional hGlyRs together with unmutated α1 or α1 plus β subunits. These aberrant receptors exhibit significantly reduced glycine sensitivity. To our knowledge, this is the first suggestion that subunits lacking TM4 domains might be incorporated into functional pentameric ligand-gated ion channel receptors.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.