Epileptic Encephalopathy In A Patient With A Novel Variant In The Kv7.2 S2 Transmembrane Segment: Clinical, Genetic, and Functional Features

Int J Mol Sci. 2019 Jul 10;20(14):3382. doi: 10.3390/ijms20143382.

Abstract

Kv7.2 subunits encoded by the KCNQ2 gene provide a major contribution to the M-current (IKM), a voltage-gated K+ current crucially involved in the regulation of neuronal excitability. Heterozygous missense variants in Kv7.2 are responsible for epileptic diseases characterized by highly heterogeneous genetic transmission and clinical severity, ranging from autosomal-dominant Benign Familial Neonatal Seizures (BFNS) to sporadic cases of severe epileptic and developmental encephalopathy (DEE). Here, we describe a patient with neonatal onset DEE, carrying a previously undescribed heterozygous KCNQ2 c.418G > C, p.Glu140Gln (E140Q) variant. Patch-clamp recordings in CHO cells expressing the E140Q mutation reveal dramatic loss of function (LoF) effects. Multistate structural modelling suggested that the E140Q substitution impeded an intrasubunit electrostatic interaction occurring between the E140 side chain in S2 and the arginine at position 210 in S4 (R210); this interaction is critically involved in stabilizing the activated configuration of the voltage-sensing domain (VSD) of Kv7.2. Functional results from coupled charge reversal or disulfide trapping experiments supported such a hypothesis. Finally, retigabine restored mutation-induced functional changes, reinforcing the rationale for the clinical use of Kv7 activators as personalized therapy for DEE-affected patients carrying Kv7.2 LoF mutations.

Keywords: Kv7 channels; coupled charge reversal; epileptic encephalopathy; homology model; retigabine; voltage sensor.

Publication types

  • Case Reports

MeSH terms

  • Amino Acid Substitution
  • Biomarkers
  • Brain Diseases / diagnosis
  • Brain Diseases / genetics*
  • Brain Diseases / therapy
  • Child, Preschool
  • Developmental Disabilities / diagnosis
  • Developmental Disabilities / genetics*
  • Developmental Disabilities / therapy
  • Electroencephalography
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Humans
  • Infant
  • Infant, Newborn
  • KCNQ2 Potassium Channel / chemistry
  • KCNQ2 Potassium Channel / genetics*
  • Loss of Function Mutation
  • Magnetic Resonance Imaging
  • Male
  • Models, Molecular
  • Neuroimaging
  • Protein Conformation
  • Protein Interaction Domains and Motifs / genetics*
  • Spasms, Infantile / diagnosis
  • Spasms, Infantile / genetics*
  • Spasms, Infantile / therapy
  • Structure-Activity Relationship
  • Symptom Assessment

Substances

  • Biomarkers
  • KCNQ2 Potassium Channel