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

A Corrigendum to this article was published on 25 February 2015

This article has been updated

Abstract

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 toe1,2. Here we report damaging de novo mutations in KCNH1 (encoding a protein called ether à go-go, EAG1 or KV10.1), 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 reports3,4,5,6,7,8, this finding demonstrates that the etiology of many unresolved CNS disorders, including epilepsies, might be explained by pathogenic mosaic mutations.

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Figure 1: Phenotypic features of TBS.
Figure 2: KCNH1 mutations in subjects with TBS.
Figure 3: Mutant KCNH1 channels show a decreased activation threshold and delayed deactivation.

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Change history

  • 06 February 2015

    In the version of this article initially published, in Figure 2a, the order of the protein alterations for variants c.1465C>T and c.1480A>G was inverted. The correct protein alterations for these two variants are p.Leu489Phe and p.Ile494Val, respectively. This error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We would like to thank the patients and their families for their participation in this study. Computational support was provided by the NeCTAR Genomics Virtual Laboratory and QRIScloud programs. We thank the Queensland Centre for Medical Genomics and Institute for Molecular Bioscience sequencing facility teams for their assistance with this project and J. Lynch for providing access to his patch-clamp facilities. We also wish to thank J. Vandenberg for his helpful discussion of results. R.J.T. was supported by an Australian Research Council Discovery Early-Career Research Award. L.M. is supported by an Australian National Health and Medical Research Council (NHMRC) C.J. Martin fellowship. A.J. and F.-G.D. were supported by a Fund Invest for Scientific Research (FIRS) grant from Centre Hospitalier Universitaire of Liége, Belgium. This work was supported in part by a University of Queensland Foundation Research Excellence Award and a donation by Joan and Graham J. Crawford.

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Authors

Contributions

C.S., R.J.T., M.T.G. and J.M. conceived and designed the project. M.T.G., J.M., Y.A., A.J., F.-G.D., A.V., J.S., G.Y., S.G. and A.Y. phenotyped the cases, provided clinical samples and provided clinical information. D.M. and S.M.G. were responsible for exome sequencing. C.S. performed all exome and variant analysis, with input from R.J.T. J.G.C. provided software and advice for sequence analysis. J.C., B.C.-A. and K.R. performed Sanger sequencing and constructed the expression vectors. L.D.R., L.M. and G.F.K. conceived the electrophysiology experiments, which were performed by L.D.R., B.C.-A. and L.M. J.C. prepared samples for targeted amplicon sequencing. Amplicon data analysis was performed by C.S. and G.J.B. All data were reviewed and synthesized by C.S. and R.J.T. The manuscript was drafted by C.S. and R.J.T. with input from M.T.G. and L.D.R. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Cas Simons or Ryan J Taft.

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Competing interests

R.J.T. became an employee of Illumina, Inc., during the course of this project.

Integrated supplementary information

Supplementary Figure 1 Activation, deactivation and Inactivation of wild-type and mutant KCNH1 channels expressed in Xenopus oocytes.

(a) Representative families of whole-cell currents showing voltage-dependent activation of wild-type (WT) and mutant human KCNH1 channels expressed in Xenopus oocytes. Currents were elicited by steps from –120 mV to +80 mV in 20-mV increments, using a holding potential of –100 mV. Inset in the final panel: schematic of the pulse protocol used for the activation experiments. (b) Representative families of whole-cell currents showing only minor steady-state inactivation of WT and mutant KCNH1 channels expressed in Xenopus oocytes. Inset in the final panel: schematic of the pulse protocol used for the inactivation experiments. (c) Activation current-voltage relationship (± s.e.m.) for WT, p.Lys217Asn, p.Leu489Phe, p.Ile494Val and p.Gln503Arg channels expressed in Xenopus oocytes. Currents were measured at the end of the activation test pulse. (d) Fast and slow time constants (τ) of deactivation for WT and mutant KCNH1 channels expressed in Xenopus oocytes, analyzed from the tail current at –90 mV following a maximally activating prepulse to +80 mV. (e) Steady-state inactivation current-voltage relationship (± s.e.m.) for WT and mutant KCNH1 channels expressed in Xenopus oocytes. Currents were measured at the end of the +30 mV activation test pulse. Data are presented as mean ± s.e.m. with the numbers of experiments indicated in parentheses. P values were calculated in comparison to WT using an unpaired t test with Welch’s correction. *P < 0.05, **P < 0.01, ***P < 0.001.

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Simons, C., Rash, L., Crawford, J. et al. Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy. Nat Genet 47, 73–77 (2015). https://doi.org/10.1038/ng.3153

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