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De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy
- Source :
- Nature genetics, Nature genetics 47(4), 393-399 (2015). doi:10.1038/ng.3239, Nature Genetics, Syrbe, S, Hedrich, U B S, Riesch, E, Djémié, T, Müller, S, Møller, R S, Maher, B, Hernandez-Hernandez, L, Synofzik, M, Caglayan, H S, Arslan, M, Serratosa, J M, Nothnagel, M, May, P, Krause, R, Löffler, H, Detert, K, Dorn, T, Vogt, H, Krämer, G, Schöls, L, Mullis, P E, Linnankivi, T, Lehesjoki, A-E, Sterbova, K, Craiu, D C, Hoffman-Zacharska, D, Korff, C M, Weber, Y G, Steinlin, M, Gallati, S, Bertsche, A, Bernhard, M K, Merkenschlager, A, Kiess, W, Gonzalez, M, Züchner, S, Palotie, A, Suls, A, De Jonghe, P, Helbig, I, Biskup, S, Wolff, M, Maljevic, S, Schüle, R, Sisodiya, S M, Weckhuysen, S, Lerche, H, Lemke, J R & EuroEPINOMICS RES Consortium 2015, ' De novo loss-or gain-of-function mutations in KCNA2 cause epileptic encephalopathy ', Nature Genetics, vol. 47, no. 4, pp. 393–399 . https://doi.org/10.1038/ng.3239, Nature Genetics, Vol. 47, No 4 (2015) pp. 393-399
- Publication Year :
- 2015
-
Abstract
- Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features(1-6). Using next-generation sequencing, we identified four different de novo mutations in KCNA2, encoding the potassium channel K(V)1.2, in six isolated patients with epileptic encephalopathy (one mutation recurred three times independently). Four individuals presented with febrile and multiple afebrile, often focal seizure types, multifocal epileptiform discharges strongly activated by sleep, mild to moderate intellectual disability, delayed speech development and sometimes ataxia. Functional studies of the two mutations associated with this phenotype showed almost complete loss of function with a dominant-negative effect. Two further individuals presented with a different and more severe epileptic encephalopathy phenotype. They carried mutations inducing a drastic gain-of-function effect leading to permanently open channels. These results establish KCNA2 as a new gene involved in human neurodevelopmental disorders through two different mechanisms, predicting either hyperexcitability or electrical silencing of K(V)1.2-expressing neurons.
- Subjects :
- Adult
Male
Ataxia
genetics [Epilepsy]
genetics [Kv1.2 Potassium Channel]
Biology
medicine.disease_cause
Bioinformatics
Infantile
Epilepsy/genetics
Article
Spasms
Cohort Studies
Epilepsy
Young Adult
Spasms, Infantile/genetics
ddc:570
Amino Acid Sequence
Child
Child, Preschool
Female
Genetic Predisposition to Disease
Humans
Infant
Kv1.2 Potassium Channel
Pedigree
Spasms, Infantile
Mutation
Genetics
Intellectual disability
medicine
KCNA2 protein, human
Preschool
Loss function
Kv1.2 Potassium Channel/genetics
ddc:618
Genetic heterogeneity
Seizure types
genetics [Spasms, Infantile]
medicine.disease
Myoclonic epilepsy
Human medicine
medicine.symptom
Subjects
Details
- Language :
- English
- ISSN :
- 15461718 and 10614036
- Volume :
- 47
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Nature genetics
- Accession number :
- edsair.doi.dedup.....e2071fa6bcf061a00ed6950fd7b8a9a4