Trial reportThe Journal of biological chemistry2012
A novel dominant hyperekplexia mutation Y705C alters trafficking and biochemical properties of the presynaptic glycine transporter GlyT2.
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 27 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
27 citing papers in PubMed, 39 citations in OpenAlex.
- 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
- Startle Disease: New Molecular Insights into an Old Neurological Disorder.The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry · 2023Review
- Calcium-Dependent Regulation of the Neuronal Glycine Transporter GlyT2 by M2 Muscarinic Acetylcholine Receptors.Neurochemical research · 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
- Structural Determinants of the Neuronal Glycine Transporter 2 for the Selective Inhibitors ALX1393 and ORG25543.ACS chemical neuroscience · 2021Article
- Functional and Biochemical Consequences of Disease Variants in Neurotransmitter Transporters: A Special Emphasis on Folding and Trafficking Deficits.Pharmacology & therapeutics · 2021Review
- The Creatine Transporter Unfolded: A Knotty Premise in the Cerebral Creatine Deficiency Syndrome.Frontiers in synaptic neuroscience · 2020Review
- A comparison of the transport kinetics of glycine transporter 1 and glycine transporter 2.The Journal of general physiology · 2019Article
- How to rescue misfolded SERT, DAT and NET: targeting conformational intermediates with atypical inhibitors and partial releasers.Biochemical Society transactions · 2019Review
- Impaired Glycine Receptor Trafficking in Neurological Diseases.Frontiers in molecular neuroscience · 2018Review
- Modification of a Putative Third Sodium Site in the Glycine Transporter GlyT2 Influences the Chloride Dependence of Substrate Transport.Frontiers in molecular neuroscience · 2018Article
- Relax, Cool Down and Scaffold: How to Restore Surface Expression of Folding-Deficient Mutant GPCRs and SLC6 Transporters.International journal of molecular sciences · 2017Review
- A novel compound mutation in GLRA1 cause hyperekplexia in a Chinese boy- a case report and review of the literature.BMC medical genetics · 2017Article
- Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies.Neuronal signaling · 2017Review
- When transporters fail to be transported: how to rescue folding-deficient SLC6 transporters.Journal of neurology & neuromedicine · 2016Article
- Molecular basis of the dominant negative effect of a glycine transporter 2 mutation associated with hyperekplexia.The Journal of biological chemistry · 2015Article
- Presynaptic control of glycine transporter 2 (GlyT2) by physical and functional association with plasma membrane Ca2+-ATPase (PMCA) and Na+-Ca2+ exchanger (NCX).The Journal of biological chemistry · 2014Article
- A cytosolic relay of heat shock proteins HSP70-1A and HSP90β monitors the folding trajectory of the serotonin transporter.The Journal of biological chemistry · 2014Article
- Defining the blanks--pharmacochaperoning of SLC6 transporters and ABC transporters.Pharmacological research · 2014Review
Corrections and comments
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Authors and funding
23 authors at 5 institutions in 2 countries.
Funding
Abstract
Hyperekplexia or startle disease is characterized by an exaggerated startle response, evoked by tactile or auditory stimuli, producing hypertonia and apnea episodes. Although rare, this orphan disorder can have serious consequences, including sudden infant death. Dominant and recessive mutations in the human glycine receptor (GlyR) α1 gene (GLRA1) are the major cause of this disorder. However, recessive mutations in the presynaptic Na(+)/Cl(-)-dependent glycine transporter GlyT2 gene (SLC6A5) are rapidly emerging as a second major cause of startle disease. In this study, systematic DNA sequencing of SLC6A5 revealed a new dominant GlyT2 mutation: pY705C (c.2114A→G) in transmembrane domain 11, in eight individuals from Spain and the United Kingdom. Curiously, individuals harboring this mutation show significant variation in clinical presentation. In addition to classical hyperekplexia symptoms, some individuals had abnormal respiration, facial dysmorphism, delayed motor development, or intellectual disability. We functionally characterized this mutation using molecular modeling, electrophysiology, [(3)H]glycine transport, cell surface expression, and cysteine labeling assays. We found that the introduced cysteine interacts with the cysteine pair Cys-311-Cys-320 in the second external loop of GlyT2. This interaction impairs transporter maturation through the secretory pathway, reduces surface expression, and inhibits transport function. Additionally, Y705C presents altered H(+) and Zn(2+) dependence of glycine transport that may affect the function of glycinergic neurotransmission in vivo.
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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.