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

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

    Research output: Contribution to journalArticlepeer-review

    65 Citations (Scopus)

    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 reports3-8, this finding demonstrates that the etiology of many unresolved CNS disorders, including epilepsies, might be explained by pathogenic mosaic mutations.

    Original languageEnglish
    Pages (from-to)73-77
    Number of pages5
    JournalNature Genetics
    Volume47
    Issue number1
    DOIs
    Publication statusPublished - Jan 2015

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