Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome

C.K. Bauer, P. Calligari, F.C. Radio, V. Caputo, M.L. Dentici, N. Falah, F. High, F. Pantaleoni, S. Barresi, A. Ciolfi, S. Pizzi, A. Bruselles, R. Person, S. Richards, M.T. Cho, D.J. Claps Sepulveda, S. Pro, R. Battini, G. Zampino, M.C. DigilioG. Bocchinfuso, B. Dallapiccola, L. Stella, M. Tartaglia

Research output: Contribution to journalArticlepeer-review


Aberrant activation or inhibition of potassium (K+) currents across the plasma membrane of cells has been causally linked to altered neurotransmission, cardiac arrhythmias, endocrine dysfunction, and (more rarely) perturbed developmental processes. The K+ channel subfamily K member 4 (KCNK4), also known as TRAAK (TWIK-related arachidonic acid-stimulated K+ channel), belongs to the mechano-gated ion channels of the TRAAK/TREK subfamily of two-pore-domain (K2P) K+ channels. While K2P channels are well known to contribute to the resting membrane potential and cellular excitability, their involvement in pathophysiological processes remains largely uncharacterized. We report that de novo missense mutations in KCNK4 cause a recognizable syndrome with a distinctive facial gestalt, for which we propose the acronym FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth). Patch-clamp analyses documented a significant gain of function of the identified KCNK4 channel mutants basally and impaired sensitivity to mechanical stimulation and arachidonic acid. Co-expression experiments indicated a dominant behavior of the disease-causing mutations. Molecular dynamics simulations consistently indicated that mutations favor sealing of the lateral intramembrane fenestration that has been proposed to negatively control K+ flow by allowing lipid access to the central cavity of the channel. Overall, our findings illustrate the pleiotropic effect of dysregulated KCNK4 function and provide support to the hypothesis of a gating mechanism based on the lateral fenestrations of K2P channels. © 2018 American Society of Human Genetics
Original languageEnglish
Pages (from-to)621-630
Number of pages10
JournalAmerican Journal of Human Genetics
Issue number4
Publication statusPublished - 2018


  • channelopathy
  • epilepsy
  • FHEIG syndrome
  • gingival overgrowth
  • hypertrichosis
  • intellectual disability
  • K2P channels
  • neurodevelopmental disorder
  • alanine
  • arachidonic acid
  • complementary DNA
  • glutamine
  • polyunsaturated fatty acid
  • proline
  • amino acid substitution
  • Article
  • case report
  • cell adhesion
  • channel gating
  • child
  • clinical article
  • clinical feature
  • conformational transition
  • developmental delay
  • DNA determination
  • face dysmorphia
  • facies
  • female
  • gain of function mutation
  • gene location
  • genetic variability
  • gestalt psychology
  • gingiva overgrowth
  • human
  • infant
  • intellectual impairment
  • KCNK4 gene
  • male
  • mechanical stimulation
  • membrane potential
  • missense mutation
  • molecular dynamics
  • mutational analysis
  • patch clamp technique
  • pleiotropy
  • point mutation
  • preschool child
  • priority journal
  • protein function
  • Sanger sequencing
  • school child
  • sensitivity analysis
  • whole exome sequencing


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