title: Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy.
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.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Cas
authors.identifier: 0000000331478042
authors.initials: C
authors.lastname: Simons
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Lachlan D
authors.initials: LD
authors.lastname: Rash
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Joanna
authors.initials: J
authors.lastname: Crawford
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Linlin
authors.initials: L
authors.lastname: Ma
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Ben
authors.initials: B
authors.lastname: Cristofori-Armstrong
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Miller
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Kelin
authors.initials: K
authors.lastname: Ru
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Baillie
authors.affiliation: Pediatric Genetics, Department of Pediatrics, Acibadem University School of Medicine, Istanbul, Turkey.
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Alanay
authors.affiliation: Center for Human Genetics, Centre Hospitalier Universitaire and University of Liège, Liège, Belgium.
authors.forename: Adeline
authors.initials: A
authors.lastname: Jacquinet
authors.affiliation: Center for Human Genetics, Centre Hospitalier Universitaire and University of Liège, Liège, Belgium.
authors.forename: François-Guillaume
authors.initials: FG
authors.lastname: Debray
authors.affiliation: 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.
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
authors.affiliation: Medical Genetics and Metabolism, Children's Hospital Central California, Madera, California, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Medical Genetics, Bezmialem Vakif University School of Medicine, Istanbul, Turkey.
authors.forename: Gözde
authors.initials: G
authors.lastname: Yesil
authors.affiliation: Department of Medical Genetics, Bezmialem Vakif University School of Medicine, Istanbul, Turkey.
authors.forename: Serhat
authors.initials: S
authors.lastname: Guler
authors.affiliation: Department of Medical Genetics, Bezmialem Vakif University School of Medicine, Istanbul, Turkey.
authors.forename: Adnan
authors.initials: A
authors.lastname: Yuksel
authors.affiliation: Real Time Genomics, Ltd., Hamilton, New Zealand.
authors.forename: John G
authors.initials: JG
authors.lastname: Cleary
authors.affiliation: 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.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Grimmond
authors.affiliation: 1] Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. [2] School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Julie
authors.initials: J
authors.lastname: McGaughran
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Glenn F
authors.initials: GF
authors.lastname: King
authors.affiliation: 1] Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. [2] School of Medicine, Griffith University, Gold Coast, Queensland, Australia.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Gabbett
authors.affiliation: 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.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Taft
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D002675:Child, Preschool; D017124:Conserved Sequence; D004827:Epilepsy / Q000235:genetics*; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D005091:Exons / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006214:Hallux / Q000002:abnormalities*; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009030:Mosaicism; D020125:Mutation, Missense; D009264:Nails, Malformed / Q000235:genetics*; D009865:Oocytes; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013933:Thumb / Q000002:abnormalities*; D014982:Xenopus laevis
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D011993:Recombinant Fusion Proteins