Trial reportThe Journal of biological chemistry2012
Mutations in the GlyT2 gene (SLC6A5) are a second major cause of startle disease.
Trial report in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
45 citing papers in PubMed, 82 citations in OpenAlex.
- Mechanisms of transport and analgesic compounds recognition by glycine transporter 2.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- A New GlyT2 Variant Associated with Hyperekplexia.International journal of molecular sciences · 2025Article
- The emerging role of glycine receptor α2 subunit defects in neurodevelopmental disorders.Frontiers in molecular neuroscience · 2025Review
- Article
- Startle Disease: New Molecular Insights into an Old Neurological Disorder.The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry · 2023Review
- Glycine: The Smallest Anti-Inflammatory Micronutrient.International journal of molecular sciences · 2023Review
- Loss-of-Function Variants inCells · 2023Article
- ReducedFrontiers in cell and developmental biology · 2022Article
- Molecular and Clinical Repercussions of GABA Transporter 1 Variants Gone Amiss: Links to Epilepsy and Developmental Spectrum Disorders.Frontiers in molecular biosciences · 2022Review
- The presynaptic glycine transporter GlyT2 is regulated by the Hedgehog pathway in vitro and in vivo.Communications biology · 2021Article
- 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
- Inhibition of Glycine Re-Uptake: A Potential Approach for Treating Pain by Augmenting Glycine-Mediated Spinal Neurotransmission and Blunting Central Nociceptive Signaling.Biomolecules · 2021Review
- Functional and Biochemical Consequences of Disease Variants in Neurotransmitter Transporters: A Special Emphasis on Folding and Trafficking Deficits.Pharmacology & therapeutics · 2021Review
- 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
- Photoswitchable ORG25543 Congener Enables Optical Control of Glycine Transporter 2.ACS chemical neuroscience · 2020Article
- C.292G>A, a novel glycine receptor alpha 1 subunit gene (GLRA1) mutation found in a Chinese patient with hyperekplexia: A case report.Medicine · 2020Article
- The synthetic cannabinoid dehydroxylcannabidiol restores the function of a major GABAThe Journal of biological chemistry · 2020Article
- Gene Expression Profiling of B Cell Lymphoma in Dogs Reveals Dichotomous Metabolic Signatures Distinguished by Oxidative Phosphorylation.Frontiers in oncology · 2020Article
- Glycinergic Transmission in the Presence and Absence of Functional GlyT2: Lessons From the Auditory Brainstem.Frontiers in synaptic neuroscience · 2020Article
- Glycine receptor autoantibodies disrupt inhibitory neurotransmission.Brain : a journal of neurology · 2019Article
Corrections and comments
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Authors and funding
30 authors at 20 institutions in 11 countries.
Funding
Abstract
Hereditary hyperekplexia or startle disease is characterized by an exaggerated startle response, evoked by tactile or auditory stimuli, leading to hypertonia and apnea episodes. Missense, nonsense, frameshift, splice site mutations, and large deletions in the human glycine receptor α1 subunit gene (GLRA1) are the major known cause of this disorder. However, mutations are also found in the genes encoding the glycine receptor β subunit (GLRB) and the presynaptic Na(+)/Cl(-)-dependent glycine transporter GlyT2 (SLC6A5). In this study, systematic DNA sequencing of SLC6A5 in 93 new unrelated human hyperekplexia patients revealed 20 sequence variants in 17 index cases presenting with homozygous or compound heterozygous recessive inheritance. Five apparently unrelated cases had the truncating mutation R439X. Genotype-phenotype analysis revealed a high rate of neonatal apneas and learning difficulties associated with SLC6A5 mutations. From the 20 SLC6A5 sequence variants, we investigated glycine uptake for 16 novel mutations, confirming that all were defective in glycine transport. Although the most common mechanism of disrupting GlyT2 function is protein truncation, new pathogenic mechanisms included splice site mutations and missense mutations affecting residues implicated in Cl(-) binding, conformational changes mediated by extracellular loop 4, and cation-π interactions. Detailed electrophysiology of mutation A275T revealed that this substitution results in a voltage-sensitive decrease in glycine transport caused by lower Na(+) affinity. This study firmly establishes the combination of missense, nonsense, frameshift, and splice site mutations in the GlyT2 gene as the second major cause of startle disease.
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Registered trials
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.