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De novo KCNB1 mutations in epileptic encephalopathy.

Annals of neurology | Dec 11, 2014

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 KV 2.1 voltage-gated potassium channel. Functional studies demonstrated a deleterious effect of the mutation on KV 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 KV 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.

Pubmed ID: 25164438 RIS Download

Mesh terms: Animals | Biotinylation | CHO Cells | Child | Child, Preschool | Cricetulus | Developmental Disabilities | Epilepsy | Female | Genetic Predisposition to Disease | Humans | Male | Membrane Potentials | Mutation, Missense | Patch-Clamp Techniques | Phenotype | Shab Potassium Channels | Transfection

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Associated grants

  • Agency: NHGRI NIH HHS, Id: U01 HG006476
  • Agency: NINDS NIH HHS, Id: R01 NS032387
  • Agency: NCRR NIH HHS, Id: UL1 RR025774
  • Agency: NIGMS NIH HHS, Id: T32 GM007347
  • Agency: NINDS NIH HHS, Id: R01 NS053792
  • Agency: NINDS NIH HHS, Id: F31 NS083097

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