De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy
Open accessAbstract
Malignant migrating partial seizures of infancy (MMPSI) is a rare epileptic encephalopathy of infancy that combines pharmacoresistant seizures with developmental delay. We performed exome sequencing in three probands with MMPSI and identified de novo gain-of-function mutations affecting the C-terminal domain of the KCNT1 potassium channel. We sequenced KCNT1 in 9 additional individuals with MMPSI and identified mutations in 4 of them, in total identifying mutations in 6 out of 12 unrelated affected individuals. Functional studies showed that the mutations led to constitutive activation of the channel, mimicking the effects of phosphorylation of the C-terminal domain by protein kinase C. In addition to regulating ion flux, KCNT1 has a non-conducting function, as its C terminus interacts with cytoplasmic proteins involved in developmental signaling pathways. These results provide a focus for future diagnostic approaches and research for this devastating condition.
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Functional studies show a range of GOFs due to increased potassium current amplitude, correlating with phenotypic severity in KCNT1 DEEs.
“Functional studies show a range of GOFs due to increased potassium current amplitude, correlating with phenotypic severity 56,58 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [56]
The indexed paper’s functional-results passage (labeled Abstract; page unavailable) reports that two KCNT1 mutations produced currents 2–3 times greater than wild type, supporting gain of function through increased current amplitude. It does not establish a range of gain-of-function effects correlated with phenotypic severity in KCNT1 developmental and epileptic encephalopathies. (LLM, conf=0.87)
Experimental — accuracy not yet measuredHeterozygous de novo pathogenic variants in KCNT1 cause a spectrum of DEEs from Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) to sleep-related hypermotor epilepsy (SHE).
“Heterozygous de novo pathogenic variants in KCNT1, encoding a sodium-activated potassium channel, cause a spectrum of DEEs from Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) to sleep-related hypermotor epilepsy (SHE) 56,57 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [56]
The indexed passage describing the sequencing results (labeled Abstract; page unavailable) reports heterozygous de novo KCNT1 variants in patients with malignant migrating partial seizures of infancy (MMPSI), an early-onset epileptic encephalopathy. The paper does not report sleep-related hypermotor epilepsy or establish the claimed spectrum extending to it. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSCN2A was the second most commonly mutated gene for EIMFS in our cohort, after KCNT1.
“Seven patients with SCN2A mutations had EIMFS, constituting 26% (7/27) of our total cohort of patients with EIMFS and rendering SCN2A the second most commonly mutated gene for EIMFS, after KCNT1.25,26”
From <i>SCN2A</i> encephalopathy: A major cause of epilepsy of infancy with migrating focal seizures (2015) · cites this paper as [25]
Seven patients with SCN2A mutations had EIMFS, constituting 26% (7/27) of the total cohort of patients with EIMFS.
“Seven patients with SCN2A mutations had EIMFS, constituting 26% (7/27) of our total cohort of patients with EIMFS and rendering SCN2A the second most commonly mutated gene for EIMFS, after KCNT1.25,26”
From <i>SCN2A</i> encephalopathy: A major cause of epilepsy of infancy with migrating focal seizures (2015) · cites this paper as [25]
Phenotypic features that distinguish SCN2A-associated EIMFS from KCNT1-associated EIMFS include severe movement disorders and response to phenytoin in some patients.
“Phenotypic features that distinguish SCN2A-associated EIMFS from KCNT1-associated EIMFS 25 include severe movement disorders and response to phenytoin in some patients.”
From <i>SCN2A</i> encephalopathy: A major cause of epilepsy of infancy with migrating focal seizures (2015) · cites this paper as [25]
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- Authors
- Barcia, G., Fleming, M. R., Deligniere, A., Gazula, V.-R., Brown, M. R., Langouet, M., Chen, H., Kronengold, J., Abhyankar, A., Cilio, R., Nitschke, P., Kaminska, A., Boddaert, N., Casanova, J.-L., Desguerre, I., Munnich, A., Dulac, O., Kaczmarek, L. K., Colleaux, L., & Nabbout, R.
- Affiliations
- Hôpital Necker-Enfants Malades (FR)
- Yale University (US)
- State University of New York (US)
- Rockefeller University (US)
- Corresponding author
- Nabbout, Rima
- ORCID
- Venue
- Nature Genetics
- Published
- 2012-10-21
- Volume
- 44
- Issue
- 11
- Pages
- 1255-1259
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3687547
- OpenAlex
- W2034651748
- Cited by
- 525
- References
- 51
- Citations by year
- 2026: 23 · 2025: 32 · 2024: 36 · 2023: 36 · 2022: 34 · 2021: 38 · 2020: 58 · 2019: 38 · 2018: 32 · 2017: 42 · 2016: 36 · 2015: 44 · 2014: 43 · 2013: 29 · 2012: 1
- FWCI
- 26.64
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Funders
- FRAXA Research Foundation
- St. Giles Foundation
- Agence Nationale de la Recherche
- Centre National de la Recherche Scientifique
- Center for Clinical and Translational Sciences, University of Texas Health Science Center at Houston
- National Institute on Deafness and Other Communication Disorders (DC01919, R01DC001919)
- National Institute of Neurological Disorders and Stroke (R21NS073943, NS073943)
- National Center for Research Resources (UL1RR024143)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD067517, R01HD067517)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- KCNT1, gain-of-function mutations, de novo mutations, epileptic encephalopathy, developmental delay, C-terminal domain, protein kinase C phosphorylation, potassium channels, developmental signaling pathways
- MeSH terms
- Animals, Cells, Cultured, Electroencephalography, Epilepsies, Partial, Humans, Infant, Infant, Newborn, Mutation, Neurons, Phosphorylation, Protein Kinase C, Xenopus, Signal Transduction, Mice, Rats, Intermediate-Conductance Calcium-Activated Potassium Channels, Exome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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