Journal Article

Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy

Ma, Linlin, Gabbett, Michael T, Alanay, Yasemin, Miller, David, Guler, Serhat, Verloes, Alain, Debray, François-Guillaume, Ru, Kelin, Baillie, Gregory J, Rash, Lachlan D, McGaughran, Julie, Simons, Cas, Shen, Joseph, Yuksel, Adnan, Crawford, Joanna, King, Glenn F, Grimmond, Sean M, Taft, Ryan J, Yesil, Gözde, Cleary, John G, Cristofori-Armstrong, Ben, Jacquinet, Adeline

2015

Overview

Cas Simons, Ryan Taft and colleagues report the identification of KCNH1 mutations in six individuals with Temple-Baraitser syndrome (TBS). Electrophysiological measurements of cells expressing mutant KCNH1 channels show decreased activation thresholds and slower deactivation in comparison to wild-type channels, suggesting that these mutations lead to gain of function of KCNH1. Temple-Baraitser syndrome (TBS) is a multisystem developmental disorder characterized by intellectual disability, epilepsy, and hypoplasia or aplasia of the nails of the thumb and great toe 1 , 2 . Here we report damaging de novo mutations in KCNH1 (encoding a protein called ether à go-go, EAG1 or K V 10.1), a voltage-gated potassium channel that is predominantly expressed in the central nervous system (CNS), in six individuals with TBS. Characterization of the mutant channels in both Xenopus laevis oocytes and human HEK293T cells showed a decreased threshold of activation and delayed deactivation, demonstrating that TBS-associated KCNH1 mutations lead to deleterious gain of function. Consistent with this result, we find that two mothers of children with TBS, who have epilepsy but are otherwise healthy, are low-level (10% and 27%) mosaic carriers of pathogenic KCNH1 mutations. Consistent with recent reports 3 , 4 , 5 , 6 , 7 , 8 , this finding demonstrates that the etiology of many unresolved CNS disorders, including epilepsies, might be explained by pathogenic mosaic mutations.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/109 / 45/70 / 45/77 / 631/208/1516 / 64/114 / 692/699/375/178 / 692/699/375/2764 / 9/74 / Agriculture / Amino Acid Sequence / Animal Genetics and Genomics / Animals / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cell cycle / Central nervous system / Child / Child, Preschool / Colleges & universities / Conserved Sequence / Development and progression / Epilepsy / Epilepsy - genetics / Ether-A-Go-Go Potassium Channels - chemistry / Ether-A-Go-Go Potassium Channels - genetics / Ether-A-Go-Go Potassium Channels - physiology / Ethics / Exons - genetics / Families & family life / Female / Gene Function / Gene mutations / Genetic aspects / Genetics & genetic processes / Génétique & processus génétiques / Hallux - abnormalities / Health aspects / HEK293 Cells / Human Genetics / Humans / Infant / Intellectual Disability - genetics / letter / Life sciences / Male / Molecular Sequence Data / Mosaicism / Mutation / Mutation, Missense / Nails, Malformed - genetics / Oocytes / Physiological aspects / Protein Conformation / Recombinant Fusion Proteins - metabolism / Risk factors / Sciences du vivant / Sequence Homology, Amino Acid / Thumb - abnormalities / Voltage-gated potassium channels / Xenopus laevis