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Nat Genet. 2015 Jan;47(1):73-7. doi: 10.1038/ng.3153. Epub 2014 Nov 24.

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

Author information

1
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
2
1] Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. [2] Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
3
Pediatric Genetics, Department of Pediatrics, Acibadem University School of Medicine, Istanbul, Turkey.
4
Center for Human Genetics, Centre Hospitalier Universitaire and University of Liège, Liège, Belgium.
5
1] Department of Genetics, Assistance Publique des Hôpitaux de Paris (AP-HP), Robert Debré Hospital, Paris, France. [2] INSERM UMR 1141, Robert Debré Hospital, Paris, France.
6
Medical Genetics and Metabolism, Children's Hospital Central California, Madera, California, USA.
7
Department of Medical Genetics, Bezmialem Vakif University School of Medicine, Istanbul, Turkey.
8
Real Time Genomics, Ltd., Hamilton, New Zealand.
9
1] Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. [2] Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Glasgow, UK.
10
1] Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. [2] School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
11
1] Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. [2] School of Medicine, Griffith University, Gold Coast, Queensland, Australia.
12
1] Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. [2] Department of Integrated Systems Biology, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA. [3] Department of Pediatrics, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA. [4] Illumina, Inc., San Diego, California, USA.

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

PMID:
25420144
DOI:
10.1038/ng.3153
[Indexed for MEDLINE]

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