De novo KCNB1 mutations in epileptic encephalopathy

Ali Torkamani, Kevin Bersell, Benjamin S. Jorge, Robert L. Bjork, Jennifer R. Friedman, Cinnamon S. Bloss, Julie Cohen, Siddharth Gupta, Sakkubai Naidu, Carlos Guillermo Vanoye, Alfred L George Jr, Jennifer A Kearney*

*Corresponding author for this work

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Objective: Numerous studies have demonstrated increased load of de novo copy number variants or single nucleotide variants in individuals with neurodevelopmental disorders, including epileptic encephalopathies, intellectual disability, and autism. Methods: We searched for de novo mutations in a family quartet with a sporadic case of epileptic encephalopathy with no known etiology to determine the underlying cause using high-coverage whole exome sequencing (WES) and lower-coverage whole genome sequencing. Mutations in additional patients were identified by WES. The effect of mutations on protein function was assessed in a heterologous expression system. Results: We identified a de novo missense mutation in KCNB1 that encodes the K V 2.1 voltage-gated potassium channel. Functional studies demonstrated a deleterious effect of the mutation on K V 2.1 function leading to a loss of ion selectivity and gain of a depolarizing inward cation conductance. Subsequently, we identified 2 additional patients with epileptic encephalopathy and de novo KCNB1 missense mutations that cause a similar pattern of K V 2.1 dysfunction. Interpretation: Our genetic and functional evidence demonstrate that KCNB1 mutation can result in early onset epileptic encephalopathy. This expands the locus heterogeneity associated with epileptic encephalopathies and suggests that clinical WES may be useful for diagnosis of epileptic encephalopathies of unknown etiology.

Original languageEnglish (US)
Pages (from-to)529-540
Number of pages12
JournalAnnals of Neurology
Volume76
Issue number4
DOIs
StatePublished - Oct 1 2014

Fingerprint

Brain Diseases
Exome
Mutation
Missense Mutation
Voltage-Gated Potassium Channels
Autistic Disorder
Intellectual Disability
Cations
Nucleotides
Genome
Ions
Proteins

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Torkamani, A., Bersell, K., Jorge, B. S., Bjork, R. L., Friedman, J. R., Bloss, C. S., ... Kearney, J. A. (2014). De novo KCNB1 mutations in epileptic encephalopathy. Annals of Neurology, 76(4), 529-540. https://doi.org/10.1002/ana.24263
Torkamani, Ali ; Bersell, Kevin ; Jorge, Benjamin S. ; Bjork, Robert L. ; Friedman, Jennifer R. ; Bloss, Cinnamon S. ; Cohen, Julie ; Gupta, Siddharth ; Naidu, Sakkubai ; Vanoye, Carlos Guillermo ; George Jr, Alfred L ; Kearney, Jennifer A. / De novo KCNB1 mutations in epileptic encephalopathy. In: Annals of Neurology. 2014 ; Vol. 76, No. 4. pp. 529-540.
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Torkamani, A, Bersell, K, Jorge, BS, Bjork, RL, Friedman, JR, Bloss, CS, Cohen, J, Gupta, S, Naidu, S, Vanoye, CG, George Jr, AL & Kearney, JA 2014, 'De novo KCNB1 mutations in epileptic encephalopathy', Annals of Neurology, vol. 76, no. 4, pp. 529-540. https://doi.org/10.1002/ana.24263

De novo KCNB1 mutations in epileptic encephalopathy. / Torkamani, Ali; Bersell, Kevin; Jorge, Benjamin S.; Bjork, Robert L.; Friedman, Jennifer R.; Bloss, Cinnamon S.; Cohen, Julie; Gupta, Siddharth; Naidu, Sakkubai; Vanoye, Carlos Guillermo; George Jr, Alfred L; Kearney, Jennifer A.

In: Annals of Neurology, Vol. 76, No. 4, 01.10.2014, p. 529-540.

Research output: Contribution to journalArticle

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AU - George Jr, Alfred L

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Torkamani A, Bersell K, Jorge BS, Bjork RL, Friedman JR, Bloss CS et al. De novo KCNB1 mutations in epileptic encephalopathy. Annals of Neurology. 2014 Oct 1;76(4):529-540. https://doi.org/10.1002/ana.24263