ArticleNature medicine2015
Chemical corrector treatment ameliorates increased seizure susceptibility in a mouse model of familial epilepsy.
Article in Nature medicine, 2015. 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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Who cites it
35 citing papers in PubMed, 94 citations in OpenAlex.
- Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.Brain : a journal of neurology · 2025Article
- Structural insights into heterohexameric assembly of epilepsy-related ligand-receptor complex LGI1-ADAM22.eLife · 2025Article
- Impact of ER stress and the unfolded protein response on Fabry disease.EBioMedicine · 2025Review
- Activity-driven synaptic translocation of LGI1 controls excitatory neurotransmission.Cell reports · 2024Article
- Oligodendrocyte-derived LGI3 and its receptor ADAM23 organize juxtaparanodal Kv1 channel clustering for short-term synaptic plasticity.Cell reports · 2024Article
- Updates on Aβ Processing by Hsp90, BRICHOS, and Newly Reported Distinctive Chaperones.Biomolecules · 2023Review
- Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- A patient-derived mutation of epilepsy-linked LGI1 increases seizure susceptibility through regulating KCell & bioscience · 2023Article
- Article
- Proposed mechanisms of tau: relationships to traumatic brain injury, Alzheimer's disease, and epilepsy.Frontiers in neurology · 2023Article
- Developmental and epileptic encephalopathies - therapeutic consequences of genetic testing.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2022Article
- Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy.Brain : a journal of neurology · 2022Article
- Disruption of the Ubiquitin-Proteasome System and Elevated Endoplasmic Reticulum Stress in Epilepsy.Biomedicines · 2022Review
- A novel LGI1 mutation causing autosomal dominant lateral temporal lobe epilepsy confirmed by a precise knock-in mouse model.CNS neuroscience & therapeutics · 2022Article
- Molecular typing of familial temporal lobe epilepsy.World journal of psychiatry · 2022Review
- A Review of Targeted Therapies for Monogenic Epilepsy Syndromes.Frontiers in neurology · 2022Review
- Restoration of Sarco/Endoplasmic Reticulum CaFrontiers in pharmacology · 2022Article
- The LGI1 protein: molecular structure, physiological functions and disruption-related seizures.Cellular and molecular life sciences : CMLS · 2021Review
- LGI1-ADAM22-MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Insights into the mechanisms of epilepsy from structural biology of LGI1-ADAM22.Cellular and molecular life sciences : CMLS · 2020Review
Corrections and comments
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Authors and funding
14 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Epilepsy is one of the most common and intractable brain disorders. Mutations in the human gene LGI1, encoding a neuronal secreted protein, cause autosomal dominant lateral temporal lobe epilepsy (ADLTE). However, the pathogenic mechanisms of LGI1 mutations remain unclear. We classified 22 reported LGI1 missense mutations as either secretion defective or secretion competent, and we generated and analyzed two mouse models of ADLTE encoding mutant proteins representative of the two groups. The secretion-defective LGI1(E383A) protein was recognized by the ER quality-control machinery and prematurely degraded, whereas the secretable LGI1(S473L) protein abnormally dimerized and was selectively defective in binding to one of its receptors, ADAM22. Both mutations caused a loss of function, compromising intracellular trafficking or ligand activity of LGI1 and converging on reduced synaptic LGI1-ADAM22 interaction. A chemical corrector, 4-phenylbutyrate (4PBA), restored LGI1(E383A) folding and binding to ADAM22 and ameliorated the increased seizure susceptibility of the LGI1(E383A) model mice. This study establishes LGI1-related epilepsy as a conformational disease and suggests new therapeutic options for human epilepsy.
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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.