Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome

Abstract

Aberrant activation or inhibition of potassium (K þ ) 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 þ channel subfamily K member 4 (KCNK4), also known as TRAAK (TWIK-related arachidonic acid-stimulated K þ channel), belongs to the mechano-gated ion channels of the TRAAK/TREK subfamily of two-pore-domain (K2P) K þ 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 þ 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.

Whole-exome sequencing and genome-wide evolutionary analyses identify novel candidate genes associated with infrared perception in pit vipers

“…6 c), three (R38W, A43T, I47V) are located in M1, and two (L277M, I283V) are located in M4. Earlier studies reported that amino acid mutations in the transmembrane helices of K 2P channels would affect channel gating, which may blunt the channel responses to various types of gating commands 45 , 46 . Therefore, we hypothesized that the five amino acid mutations in the transmembrane helices of pit viper KCNK4 might have a similar effect.…”

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

“…Targeted enrichment (SureSelect All Exon V.4, Agilent) used genomic DNA extracted from circulating leukocytes for the affected subject and both parents, and parallel sequencing was performed using an Illumina HiSeq2000 platform, obtaining about 70 million reads. The data analysis was performed using an in-house implemented pipeline, which mainly take advantage of the Genome Analysis Toolkit (GATK V.3.7) 47 framework, as previously reported 48,49 ). The functional annotation of variants was achieved using SnpEff and dbNSFP (V.3.0) [50][51][52] .…”

Co-occurrence of mutations in KIF7 and KIAA0556 in Joubert syndrome with ocular coloboma, pituitary malformation and growth hormone deficiency: a case report and literature review

“…WES was performed using genomic DNA extracted from leukocytes of the affected subject and his parents, using the Nextera Rapid Capture Exome kit (Illumina) for library preparation, and a NextSeq500 platform (Illumina) for sequencing. WES data analysis was performed using an in-house implemented pipeline [11][12][13]. WES details and statistics are described in Supplementary Data 1 and Table S1 (Additional files).…”