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De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy.

ABSTRACT: Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features. Using next-generation sequencing, we identified four different de novo mutations in KCNA2, encoding the potassium channel KV1.2, 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 KV1.2-expressing neurons.

SUBMITTER: Syrbe S

PROVIDER: S-EPMC4380508 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy.

Syrbe Steffen S Hedrich Ulrike B S UBS Riesch Erik E Djémié Tania T Müller Stephan S Møller Rikke S RS Maher Bridget B Hernandez-Hernandez Laura L Synofzik Matthis M Caglayan Hande S HS Arslan Mutluay M Serratosa José M JM Nothnagel Michael M May Patrick P Krause Roland R Löffler Heidrun H Detert Katja K Dorn Thomas T Vogt Heinrich H Krämer Günter G Schöls Ludger L Mullis Primus E PE Linnankivi Tarja T Lehesjoki Anna-Elina AE Sterbova Katalin K Craiu Dana C DC Hoffman-Zacharska Dorota D Korff Christian M CM Weber Yvonne G YG Steinlin Maja M Gallati Sabina S Bertsche Astrid A Bernhard Matthias K MK Merkenschlager Andreas A Kiess Wieland W Gonzalez Michael M Züchner Stephan S Palotie Aarno A Suls Arvid A De Jonghe Peter P Helbig Ingo I Biskup Saskia S Wolff Markus M Maljevic Snezana S Schüle Rebecca R Sisodiya Sanjay M SM Weckhuysen Sarah S Lerche Holger H Lemke Johannes R JR

Nature genetics 20150309 4

Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features. Using next-generation sequencing, we identified four different de novo mutations in KCNA2, encoding the potassium channel KV1.2, in six isolated patients with epileptic encephalopathy (one mutation recurred three times independently). Four individuals presented with febrile and multiple afebrile, often focal seizure ...[more]

PMID: 25751627

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Project description:FZR1, which encodes the Cdh1 subunit of the anaphase-promoting complex, plays an important role in neurodevelopment by regulating the cell cycle and by its multiple post-mitotic functions in neurons. In this study, evaluation of 250 unrelated patients with developmental and epileptic encephalopathies and a connection on GeneMatcher led to the identification of three de novo missense variants in FZR1. Whole-exome sequencing in 39 patient-parent trios and subsequent targeted sequencing in an additional cohort of 211 patients was performed to identify novel genes involved in developmental and epileptic encephalopathy. Functional studies in Drosophila were performed using three different mutant alleles of the Drosophila homologue of FZR1 fzr. All three individuals carrying de novo variants in FZR1 had childhood-onset generalized epilepsy, intellectual disability, mild ataxia and normal head circumference. Two individuals were diagnosed with the developmental and epileptic encephalopathy subtype myoclonic atonic epilepsy. We provide genetic-association testing using two independent statistical tests to support FZR1 association with developmental and epileptic encephalopathies. Further, we provide functional evidence that the missense variants are loss-of-function alleles using Drosophila neurodevelopment assays. Using three fly mutant alleles of the Drosophila homologue fzr and overexpression studies, we show that patient variants can affect proper neurodevelopment. With the recent report of a patient with neonatal-onset with microcephaly who also carries a de novo FZR1 missense variant, our study consolidates the relationship between FZR1 and developmental and epileptic encephalopathy and expands the associated phenotype. We conclude that heterozygous loss-of-function of FZR1 leads to developmental and epileptic encephalopathies associated with a spectrum of neonatal to childhood-onset seizure types, developmental delay and mild ataxia. Microcephaly can be present but is not an essential feature of FZR1-encephalopathy. In summary, our approach of targeted sequencing using novel gene candidates and functional testing in Drosophila will help solve undiagnosed myoclonic atonic epilepsy or developmental and epileptic encephalopathy cases.

Dataset Information

De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy.

Publications

De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy.

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