Send to

Choose Destination
Am J Hum Genet. 2018 Oct 4;103(4):621-630. doi: 10.1016/j.ajhg.2018.09.001.

Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome.

Author information

Center for Experimental Medicine, Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address:
Department of Chemical Science and Technologies, University of Rome Tor Vergata, 00133 Rome, Italy.
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.
Division of Clinical Genetics, Nemours Children's Hospital, Orlando, FL 32827, USA.
Medical Genetics, Mass General Hospital for Children, Massachusetts General Hospital, Boston, MA 02114-2696, USA.
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
GeneDX, Gaithersburg, MD 20877, USA.
Department of Developmental Neuroscience, IRCCS Stella Maris, 56128 Calambrone, Italy.
Center for Rare Disease and Congenital Defects, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy. Electronic address:


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.


FHEIG syndrome; K2P channels; TRAAK; channelopathy; epilepsy; gingival overgrowth; hypertrichosis; intellectual disability; neurodevelopmental disorder

[Available on 2019-04-04]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center