ArticleNeurobiology of disease2013
Novel missense mutations in the glycine receptor β subunit gene (GLRB) in startle disease.
Article in Neurobiology of disease, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 56 citations in OpenAlex.
- New hyperekplexia mutations provide insight into glycine receptor assembly, trafficking, and activation mechanisms.The Journal of biological chemistry · 2013Trial
- Glycine Receptor β-Targeting Autoantibodies Contribute to the Pathology of Autoimmune Diseases.Neurology(R) neuroimmunology & neuroinflammation · 2024Article
- Role of the Glycine Receptor β Subunit in Synaptic Localization and Pathogenicity in Severe Startle Disease.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- 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
- Novel Functional Properties of Missense Mutations in the Glycine Receptor β Subunit in Startle Disease.Frontiers in molecular neuroscience · 2021Article
- Modulatory Actions of the Glycine Receptor β Subunit on the Positive Allosteric Modulation of Ethanol in α2 Containing Receptors.Frontiers in molecular neuroscience · 2021Article
- Membrane cholesterol dependence of cannabinoid modulation of glycine receptor.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Structural analysis of pathogenic missense mutations in GABRA2 and identification of a novel de novo variant in the desensitization gate.Molecular genetics & genomic medicine · 2020Article
- The synthetic cannabinoid dehydroxylcannabidiol restores the function of a major GABAThe Journal of biological chemistry · 2020Article
- Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study (IRASFS).Scientific reports · 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
- Impaired Glycine Receptor Trafficking in Neurological Diseases.Frontiers in molecular neuroscience · 2018Review
- Characterization of the Zebrafish Glycine Receptor Family Reveals Insights Into Glycine Receptor Structure Function and Stoichiometry.Frontiers in molecular neuroscience · 2018Article
- Genome-wide analysis reveals differential selection involved with copy number variation in diverse Chinese Cattle.Scientific reports · 2017Article
- A novel compound mutation in GLRA1 cause hyperekplexia in a Chinese boy- a case report and review of the literature.BMC medical genetics · 2017Article
- GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder.Molecular psychiatry · 2017Article
- Modulation of defensive reactivity by GLRB allelic variation: converging evidence from an intermediate phenotype approach.Translational psychiatry · 2017Article
- Disruption of a Structurally Important Extracellular Element in the Glycine Receptor Leads to Decreased Synaptic Integration and Signaling Resulting in Severe Startle Disease.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2017Article
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Authors and funding
15 authors at 7 institutions in 4 countries.
Funding
Abstract
Startle disease is a rare, potentially fatal neuromotor disorder characterized by exaggerated startle reflexes and hypertonia in response to sudden unexpected auditory, visual or tactile stimuli. Mutations in the GlyR α(1) subunit gene (GLRA1) are the major cause of this disorder, since remarkably few individuals with mutations in the GlyR β subunit gene (GLRB) have been found to date. Systematic DNA sequencing of GLRB in individuals with hyperekplexia revealed new missense mutations in GLRB, resulting in M177R, L285R and W310C substitutions. The recessive mutation M177R results in the insertion of a positively-charged residue into a hydrophobic pocket in the extracellular domain, resulting in an increased EC(50) and decreased maximal responses of α(1)β GlyRs. The de novo mutation L285R results in the insertion of a positively-charged side chain into the pore-lining 9' position. Mutations at this site are known to destabilize the channel closed state and produce spontaneously active channels. Consistent with this, we identified a leak conductance associated with spontaneous GlyR activity in cells expressing α(1)β(L285R) GlyRs. Peak currents were also reduced for α(1)β(L285R) GlyRs although glycine sensitivity was normal. W310C was predicted to interfere with hydrophobic side-chain stacking between M1, M2 and M3. We found that W310C had no effect on glycine sensitivity, but reduced maximal currents in α(1)β GlyRs in both homozygous (α(1)β(W310C)) and heterozygous (α(1)ββ(W310C)) stoichiometries. Since mild startle symptoms were reported in W310C carriers, this may represent an example of incomplete dominance in startle disease, providing a potential genetic explanation for the 'minor' form of hyperekplexia.
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