Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy.
Identifieur interne : 002B05 ( Main/Exploration ); précédent : 002B04; suivant : 002B06Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy.
Auteurs : Cas Simons [Australie] ; Lachlan D. Rash [Australie] ; Joanna Crawford [Australie] ; Linlin Ma [Australie] ; Ben Cristofori-Armstrong [Australie] ; David Miller [Australie] ; Kelin Ru [Australie] ; Gregory J. Baillie [Australie] ; Yasemin Alanay [Turquie] ; Adeline Jacquinet [Belgique] ; François-Guillaume Debray [Belgique] ; Alain Verloes [France] ; Joseph Shen [États-Unis] ; Gözde Yesil [Turquie] ; Serhat Guler [Turquie] ; Adnan Yuksel [Turquie] ; John G. Cleary [Nouvelle-Zélande] ; Sean M. Grimmond [Royaume-Uni] ; Julie Mcgaughran [Australie] ; Glenn F. King [Australie] ; Michael T. Gabbett [Australie] ; Ryan J. Taft [États-Unis]Source :
- Nature genetics [ 1546-1718 ] ; 2015.
Descripteurs français
- KwdFr :
- Animaux, Canaux potassiques éther-à-go-go (), Canaux potassiques éther-à-go-go (génétique), Canaux potassiques éther-à-go-go (physiologie), Cellules HEK293, Conformation des protéines, Données de séquences moléculaires, Déficience intellectuelle (génétique), Enfant, Enfant d'âge préscolaire, Exons (génétique), Femelle, Hallux (malformations), Humains, Mosaïcisme, Mutation faux-sens, Mâle, Nourrisson, Ongles malformés (génétique), Ovocytes, Pouce (malformations), Protéines de fusion recombinantes (métabolisme), Similitude de séquences d'acides aminés, Séquence conservée, Séquence d'acides aminés, Xenopus laevis, Épilepsie (génétique).
- MESH :
- génétique : Canaux potassiques éther-à-go-go, Déficience intellectuelle, Exons, Ongles malformés, Épilepsie.
- malformations : Hallux, Pouce.
- métabolisme : Protéines de fusion recombinantes.
- physiologie : Canaux potassiques éther-à-go-go.
- Animaux, Canaux potassiques éther-à-go-go, Cellules HEK293, Conformation des protéines, Données de séquences moléculaires, Enfant, Enfant d'âge préscolaire, Femelle, Humains, Mosaïcisme, Mutation faux-sens, Mâle, Nourrisson, Ovocytes, Similitude de séquences d'acides aminés, Séquence conservée, Séquence d'acides aminés, Xenopus laevis.
English descriptors
- KwdEn :
- Amino Acid Sequence, Animals, Child, Child, Preschool, Conserved Sequence, Epilepsy (genetics), Ether-A-Go-Go Potassium Channels (chemistry), Ether-A-Go-Go Potassium Channels (genetics), Ether-A-Go-Go Potassium Channels (physiology), Exons (genetics), Female, HEK293 Cells, Hallux (abnormalities), Humans, Infant, Intellectual Disability (genetics), Male, Molecular Sequence Data, Mosaicism, Mutation, Missense, Nails, Malformed (genetics), Oocytes, Protein Conformation, Recombinant Fusion Proteins (metabolism), Sequence Homology, Amino Acid, Thumb (abnormalities), Xenopus laevis.
- MESH :
- chemical , chemistry : Ether-A-Go-Go Potassium Channels.
- abnormalities : Hallux, Thumb.
- genetics : Epilepsy, Ether-A-Go-Go Potassium Channels, Exons, Intellectual Disability, Nails, Malformed.
- chemical , metabolism : Recombinant Fusion Proteins.
- chemical , physiology : Ether-A-Go-Go Potassium Channels.
- Amino Acid Sequence, Animals, Child, Child, Preschool, Conserved Sequence, Female, HEK293 Cells, Humans, Infant, Male, Molecular Sequence Data, Mosaicism, Mutation, Missense, Oocytes, Protein Conformation, Sequence Homology, Amino Acid, Xenopus laevis.
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.
DOI: 10.1038/ng.3153
PubMed: 25420144
Affiliations:
- Australie, Belgique, France, Nouvelle-Zélande, Royaume-Uni, Turquie, États-Unis
- Californie, Île-de-France
- Paris
Links toward previous steps (curation, corpus...)
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Le document en format XML
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[2] Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>New South Wales</wicri:noRegion></affiliation></author><author><name sortKey="Ru, Kelin" sort="Ru, Kelin" uniqKey="Ru K" first="Kelin" last="Ru">Kelin Ru</name><affiliation wicri:level="1"><nlm:affiliation>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Baillie, Gregory J" sort="Baillie, Gregory J" uniqKey="Baillie G" first="Gregory J" last="Baillie">Gregory J. Baillie</name><affiliation wicri:level="1"><nlm:affiliation>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Alanay, Yasemin" sort="Alanay, Yasemin" uniqKey="Alanay Y" first="Yasemin" last="Alanay">Yasemin Alanay</name><affiliation wicri:level="1"><nlm:affiliation>Pediatric Genetics, Department of Pediatrics, Acibadem University School of Medicine, Istanbul, Turkey.</nlm:affiliation><country xml:lang="fr">Turquie</country><wicri:regionArea>Pediatric Genetics, Department of Pediatrics, Acibadem University School of Medicine, Istanbul</wicri:regionArea><wicri:noRegion>Istanbul</wicri:noRegion></affiliation></author><author><name sortKey="Jacquinet, Adeline" sort="Jacquinet, Adeline" uniqKey="Jacquinet A" first="Adeline" last="Jacquinet">Adeline Jacquinet</name><affiliation wicri:level="1"><nlm:affiliation>Center for Human Genetics, Centre Hospitalier Universitaire and University of Liège, Liège, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Center for Human Genetics, Centre Hospitalier Universitaire and University of Liège, Liège</wicri:regionArea><wicri:noRegion>Liège</wicri:noRegion></affiliation></author><author><name sortKey="Debray, Francois Guillaume" sort="Debray, Francois Guillaume" uniqKey="Debray F" first="François-Guillaume" last="Debray">François-Guillaume Debray</name><affiliation wicri:level="1"><nlm:affiliation>Center for Human Genetics, Centre Hospitalier Universitaire and University of Liège, Liège, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Center for Human Genetics, Centre Hospitalier Universitaire and University of Liège, Liège</wicri:regionArea><wicri:noRegion>Liège</wicri:noRegion></affiliation></author><author><name sortKey="Verloes, Alain" sort="Verloes, Alain" uniqKey="Verloes A" first="Alain" last="Verloes">Alain Verloes</name><affiliation wicri:level="3"><nlm: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.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>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</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Shen, Joseph" sort="Shen, Joseph" uniqKey="Shen J" first="Joseph" last="Shen">Joseph Shen</name><affiliation wicri:level="2"><nlm:affiliation>Medical Genetics and Metabolism, Children's Hospital Central California, Madera, California, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Medical Genetics and Metabolism, Children's Hospital Central California, Madera, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Yesil, Gozde" sort="Yesil, Gozde" uniqKey="Yesil G" first="Gözde" last="Yesil">Gözde Yesil</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medical Genetics, Bezmialem Vakif University School of Medicine, Istanbul, Turkey.</nlm:affiliation><country xml:lang="fr">Turquie</country><wicri:regionArea>Department of Medical Genetics, Bezmialem Vakif University School of Medicine, Istanbul</wicri:regionArea><wicri:noRegion>Istanbul</wicri:noRegion></affiliation></author><author><name sortKey="Guler, Serhat" sort="Guler, Serhat" uniqKey="Guler S" first="Serhat" last="Guler">Serhat Guler</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medical Genetics, Bezmialem Vakif University School of Medicine, Istanbul, Turkey.</nlm:affiliation><country xml:lang="fr">Turquie</country><wicri:regionArea>Department of Medical Genetics, Bezmialem Vakif University School of Medicine, Istanbul</wicri:regionArea><wicri:noRegion>Istanbul</wicri:noRegion></affiliation></author><author><name sortKey="Yuksel, Adnan" sort="Yuksel, Adnan" uniqKey="Yuksel A" first="Adnan" last="Yuksel">Adnan Yuksel</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medical Genetics, Bezmialem Vakif University School of Medicine, Istanbul, Turkey.</nlm:affiliation><country xml:lang="fr">Turquie</country><wicri:regionArea>Department of Medical Genetics, Bezmialem Vakif University School of Medicine, Istanbul</wicri:regionArea><wicri:noRegion>Istanbul</wicri:noRegion></affiliation></author><author><name sortKey="Cleary, John G" sort="Cleary, John G" uniqKey="Cleary J" first="John G" last="Cleary">John G. Cleary</name><affiliation wicri:level="1"><nlm:affiliation>Real Time Genomics, Ltd., Hamilton, New Zealand.</nlm:affiliation><country xml:lang="fr">Nouvelle-Zélande</country><wicri:regionArea>Real Time Genomics, Ltd., Hamilton</wicri:regionArea><wicri:noRegion>Hamilton</wicri:noRegion></affiliation></author><author><name sortKey="Grimmond, Sean M" sort="Grimmond, Sean M" uniqKey="Grimmond S" first="Sean M" last="Grimmond">Sean M. Grimmond</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Glasgow</wicri:noRegion></affiliation></author><author><name sortKey="Mcgaughran, Julie" sort="Mcgaughran, Julie" uniqKey="Mcgaughran J" first="Julie" last="Mcgaughran">Julie Mcgaughran</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>1] Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. [2] School of Medicine, The University of Queensland, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="King, Glenn F" sort="King, Glenn F" uniqKey="King G" first="Glenn F" last="King">Glenn F. King</name><affiliation wicri:level="1"><nlm:affiliation>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Gabbett, Michael T" sort="Gabbett, Michael T" uniqKey="Gabbett M" first="Michael T" last="Gabbett">Michael T. Gabbett</name><affiliation wicri:level="1"><nlm:affiliation>1] Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. [2] School of Medicine, Griffith University, Gold Coast, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>1] Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. [2] School of Medicine, Griffith University, Gold Coast, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Taft, Ryan J" sort="Taft, Ryan J" uniqKey="Taft R" first="Ryan J" last="Taft">Ryan J. Taft</name><affiliation wicri:level="2"><nlm: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.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>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</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2015">2015</date><idno type="RBID">pubmed:25420144</idno><idno type="pmid">25420144</idno><idno type="doi">10.1038/ng.3153</idno><idno type="wicri:Area/PubMed/Corpus">003192</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">003192</idno><idno type="wicri:Area/PubMed/Curation">003082</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">003082</idno><idno type="wicri:Area/PubMed/Checkpoint">003082</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">003082</idno><idno type="wicri:Area/Ncbi/Merge">002010</idno><idno type="wicri:Area/Ncbi/Curation">002010</idno><idno type="wicri:Area/Ncbi/Checkpoint">002010</idno><idno type="wicri:Area/Main/Merge">002B05</idno><idno type="wicri:Area/Main/Curation">002B05</idno><idno type="wicri:Area/Main/Exploration">002B05</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy.</title><author><name sortKey="Simons, Cas" sort="Simons, Cas" uniqKey="Simons C" first="Cas" last="Simons">Cas Simons</name><affiliation wicri:level="1"><nlm:affiliation>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Rash, Lachlan D" sort="Rash, Lachlan D" uniqKey="Rash L" first="Lachlan D" last="Rash">Lachlan D. Rash</name><affiliation wicri:level="1"><nlm:affiliation>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Crawford, Joanna" sort="Crawford, Joanna" uniqKey="Crawford J" first="Joanna" last="Crawford">Joanna Crawford</name><affiliation wicri:level="1"><nlm:affiliation>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Ma, Linlin" sort="Ma, Linlin" uniqKey="Ma L" first="Linlin" last="Ma">Linlin Ma</name><affiliation wicri:level="1"><nlm:affiliation>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Cristofori Armstrong, Ben" sort="Cristofori Armstrong, Ben" uniqKey="Cristofori Armstrong B" first="Ben" last="Cristofori-Armstrong">Ben Cristofori-Armstrong</name><affiliation wicri:level="1"><nlm:affiliation>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Miller, David" sort="Miller, David" uniqKey="Miller D" first="David" last="Miller">David Miller</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>New South Wales</wicri:noRegion></affiliation></author><author><name sortKey="Ru, Kelin" sort="Ru, Kelin" uniqKey="Ru K" first="Kelin" last="Ru">Kelin Ru</name><affiliation wicri:level="1"><nlm:affiliation>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Baillie, Gregory J" sort="Baillie, Gregory J" uniqKey="Baillie G" first="Gregory J" last="Baillie">Gregory J. Baillie</name><affiliation wicri:level="1"><nlm:affiliation>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Alanay, Yasemin" sort="Alanay, Yasemin" uniqKey="Alanay Y" first="Yasemin" last="Alanay">Yasemin Alanay</name><affiliation wicri:level="1"><nlm:affiliation>Pediatric Genetics, Department of Pediatrics, Acibadem University School of Medicine, Istanbul, Turkey.</nlm:affiliation><country xml:lang="fr">Turquie</country><wicri:regionArea>Pediatric Genetics, Department of Pediatrics, Acibadem University School of Medicine, Istanbul</wicri:regionArea><wicri:noRegion>Istanbul</wicri:noRegion></affiliation></author><author><name sortKey="Jacquinet, Adeline" sort="Jacquinet, Adeline" uniqKey="Jacquinet A" first="Adeline" last="Jacquinet">Adeline Jacquinet</name><affiliation wicri:level="1"><nlm:affiliation>Center for Human Genetics, Centre Hospitalier Universitaire and University of Liège, Liège, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Center for Human Genetics, Centre Hospitalier Universitaire and University of Liège, Liège</wicri:regionArea><wicri:noRegion>Liège</wicri:noRegion></affiliation></author><author><name sortKey="Debray, Francois Guillaume" sort="Debray, Francois Guillaume" uniqKey="Debray F" first="François-Guillaume" last="Debray">François-Guillaume Debray</name><affiliation wicri:level="1"><nlm:affiliation>Center for Human Genetics, Centre Hospitalier Universitaire and University of Liège, Liège, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Center for Human Genetics, Centre Hospitalier Universitaire and University of Liège, Liège</wicri:regionArea><wicri:noRegion>Liège</wicri:noRegion></affiliation></author><author><name sortKey="Verloes, Alain" sort="Verloes, Alain" uniqKey="Verloes A" first="Alain" last="Verloes">Alain Verloes</name><affiliation wicri:level="3"><nlm: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.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>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</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Shen, Joseph" sort="Shen, Joseph" uniqKey="Shen J" first="Joseph" last="Shen">Joseph Shen</name><affiliation wicri:level="2"><nlm:affiliation>Medical Genetics and Metabolism, Children's Hospital Central California, Madera, California, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Medical Genetics and Metabolism, Children's Hospital Central California, Madera, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Yesil, Gozde" sort="Yesil, Gozde" uniqKey="Yesil G" first="Gözde" last="Yesil">Gözde Yesil</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medical Genetics, Bezmialem Vakif University School of Medicine, Istanbul, Turkey.</nlm:affiliation><country xml:lang="fr">Turquie</country><wicri:regionArea>Department of Medical Genetics, Bezmialem Vakif University School of Medicine, Istanbul</wicri:regionArea><wicri:noRegion>Istanbul</wicri:noRegion></affiliation></author><author><name sortKey="Guler, Serhat" sort="Guler, Serhat" uniqKey="Guler S" first="Serhat" last="Guler">Serhat Guler</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medical Genetics, Bezmialem Vakif University School of Medicine, Istanbul, Turkey.</nlm:affiliation><country xml:lang="fr">Turquie</country><wicri:regionArea>Department of Medical Genetics, Bezmialem Vakif University School of Medicine, Istanbul</wicri:regionArea><wicri:noRegion>Istanbul</wicri:noRegion></affiliation></author><author><name sortKey="Yuksel, Adnan" sort="Yuksel, Adnan" uniqKey="Yuksel A" first="Adnan" last="Yuksel">Adnan Yuksel</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medical Genetics, Bezmialem Vakif University School of Medicine, Istanbul, Turkey.</nlm:affiliation><country xml:lang="fr">Turquie</country><wicri:regionArea>Department of Medical Genetics, Bezmialem Vakif University School of Medicine, Istanbul</wicri:regionArea><wicri:noRegion>Istanbul</wicri:noRegion></affiliation></author><author><name sortKey="Cleary, John G" sort="Cleary, John G" uniqKey="Cleary J" first="John G" last="Cleary">John G. Cleary</name><affiliation wicri:level="1"><nlm:affiliation>Real Time Genomics, Ltd., Hamilton, New Zealand.</nlm:affiliation><country xml:lang="fr">Nouvelle-Zélande</country><wicri:regionArea>Real Time Genomics, Ltd., Hamilton</wicri:regionArea><wicri:noRegion>Hamilton</wicri:noRegion></affiliation></author><author><name sortKey="Grimmond, Sean M" sort="Grimmond, Sean M" uniqKey="Grimmond S" first="Sean M" last="Grimmond">Sean M. Grimmond</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Glasgow</wicri:noRegion></affiliation></author><author><name sortKey="Mcgaughran, Julie" sort="Mcgaughran, Julie" uniqKey="Mcgaughran J" first="Julie" last="Mcgaughran">Julie Mcgaughran</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>1] Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. [2] School of Medicine, The University of Queensland, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="King, Glenn F" sort="King, Glenn F" uniqKey="King G" first="Glenn F" last="King">Glenn F. King</name><affiliation wicri:level="1"><nlm:affiliation>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Gabbett, Michael T" sort="Gabbett, Michael T" uniqKey="Gabbett M" first="Michael T" last="Gabbett">Michael T. Gabbett</name><affiliation wicri:level="1"><nlm:affiliation>1] Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. [2] School of Medicine, Griffith University, Gold Coast, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>1] Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. [2] School of Medicine, Griffith University, Gold Coast, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Taft, Ryan J" sort="Taft, Ryan J" uniqKey="Taft R" first="Ryan J" last="Taft">Ryan J. Taft</name><affiliation wicri:level="2"><nlm: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.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>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</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author></analytic><series><title level="j">Nature genetics</title><idno type="eISSN">1546-1718</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Sequence</term><term>Animals</term><term>Child</term><term>Child, Preschool</term><term>Conserved Sequence</term><term>Epilepsy (genetics)</term><term>Ether-A-Go-Go Potassium Channels (chemistry)</term><term>Ether-A-Go-Go Potassium Channels (genetics)</term><term>Ether-A-Go-Go Potassium Channels (physiology)</term><term>Exons (genetics)</term><term>Female</term><term>HEK293 Cells</term><term>Hallux (abnormalities)</term><term>Humans</term><term>Infant</term><term>Intellectual Disability (genetics)</term><term>Male</term><term>Molecular Sequence Data</term><term>Mosaicism</term><term>Mutation, Missense</term><term>Nails, Malformed (genetics)</term><term>Oocytes</term><term>Protein Conformation</term><term>Recombinant Fusion Proteins (metabolism)</term><term>Sequence Homology, Amino Acid</term><term>Thumb (abnormalities)</term><term>Xenopus laevis</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Canaux potassiques éther-à-go-go ()</term><term>Canaux potassiques éther-à-go-go (génétique)</term><term>Canaux potassiques éther-à-go-go (physiologie)</term><term>Cellules HEK293</term><term>Conformation des protéines</term><term>Données de séquences moléculaires</term><term>Déficience intellectuelle (génétique)</term><term>Enfant</term><term>Enfant d'âge préscolaire</term><term>Exons (génétique)</term><term>Femelle</term><term>Hallux (malformations)</term><term>Humains</term><term>Mosaïcisme</term><term>Mutation faux-sens</term><term>Mâle</term><term>Nourrisson</term><term>Ongles malformés (génétique)</term><term>Ovocytes</term><term>Pouce (malformations)</term><term>Protéines de fusion recombinantes (métabolisme)</term><term>Similitude de séquences d'acides aminés</term><term>Séquence conservée</term><term>Séquence d'acides aminés</term><term>Xenopus laevis</term><term>Épilepsie (génétique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Ether-A-Go-Go Potassium Channels</term></keywords><keywords scheme="MESH" qualifier="abnormalities" xml:lang="en"><term>Hallux</term><term>Thumb</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Epilepsy</term><term>Ether-A-Go-Go Potassium Channels</term><term>Exons</term><term>Intellectual Disability</term><term>Nails, Malformed</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Canaux potassiques éther-à-go-go</term><term>Déficience intellectuelle</term><term>Exons</term><term>Ongles malformés</term><term>Épilepsie</term></keywords><keywords scheme="MESH" qualifier="malformations" xml:lang="fr"><term>Hallux</term><term>Pouce</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Recombinant Fusion Proteins</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Protéines de fusion recombinantes</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Canaux potassiques éther-à-go-go</term></keywords><keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Ether-A-Go-Go Potassium Channels</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term><term>Animals</term><term>Child</term><term>Child, Preschool</term><term>Conserved Sequence</term><term>Female</term><term>HEK293 Cells</term><term>Humans</term><term>Infant</term><term>Male</term><term>Molecular Sequence Data</term><term>Mosaicism</term><term>Mutation, Missense</term><term>Oocytes</term><term>Protein Conformation</term><term>Sequence Homology, Amino Acid</term><term>Xenopus laevis</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Canaux potassiques éther-à-go-go</term><term>Cellules HEK293</term><term>Conformation des protéines</term><term>Données de séquences moléculaires</term><term>Enfant</term><term>Enfant d'âge préscolaire</term><term>Femelle</term><term>Humains</term><term>Mosaïcisme</term><term>Mutation faux-sens</term><term>Mâle</term><term>Nourrisson</term><term>Ovocytes</term><term>Similitude de séquences d'acides aminés</term><term>Séquence conservée</term><term>Séquence d'acides aminés</term><term>Xenopus laevis</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>Australie</li><li>Belgique</li><li>France</li><li>Nouvelle-Zélande</li><li>Royaume-Uni</li><li>Turquie</li><li>États-Unis</li></country><region><li>Californie</li><li>Île-de-France</li></region><settlement><li>Paris</li></settlement></list><tree><country name="Australie"><noRegion><name sortKey="Simons, Cas" sort="Simons, Cas" uniqKey="Simons C" first="Cas" last="Simons">Cas Simons</name></noRegion><name sortKey="Baillie, Gregory J" sort="Baillie, Gregory J" uniqKey="Baillie G" first="Gregory J" last="Baillie">Gregory J. Baillie</name><name sortKey="Crawford, Joanna" sort="Crawford, Joanna" uniqKey="Crawford J" first="Joanna" last="Crawford">Joanna Crawford</name><name sortKey="Cristofori Armstrong, Ben" sort="Cristofori Armstrong, Ben" uniqKey="Cristofori Armstrong B" first="Ben" last="Cristofori-Armstrong">Ben Cristofori-Armstrong</name><name sortKey="Gabbett, Michael T" sort="Gabbett, Michael T" uniqKey="Gabbett M" first="Michael T" last="Gabbett">Michael T. Gabbett</name><name sortKey="King, Glenn F" sort="King, Glenn F" uniqKey="King G" first="Glenn F" last="King">Glenn F. King</name><name sortKey="Ma, Linlin" sort="Ma, Linlin" uniqKey="Ma L" first="Linlin" last="Ma">Linlin Ma</name><name sortKey="Mcgaughran, Julie" sort="Mcgaughran, Julie" uniqKey="Mcgaughran J" first="Julie" last="Mcgaughran">Julie Mcgaughran</name><name sortKey="Miller, David" sort="Miller, David" uniqKey="Miller D" first="David" last="Miller">David Miller</name><name sortKey="Rash, Lachlan D" sort="Rash, Lachlan D" uniqKey="Rash L" first="Lachlan D" last="Rash">Lachlan D. Rash</name><name sortKey="Ru, Kelin" sort="Ru, Kelin" uniqKey="Ru K" first="Kelin" last="Ru">Kelin Ru</name></country><country name="Turquie"><noRegion><name sortKey="Alanay, Yasemin" sort="Alanay, Yasemin" uniqKey="Alanay Y" first="Yasemin" last="Alanay">Yasemin Alanay</name></noRegion><name sortKey="Guler, Serhat" sort="Guler, Serhat" uniqKey="Guler S" first="Serhat" last="Guler">Serhat Guler</name><name sortKey="Yesil, Gozde" sort="Yesil, Gozde" uniqKey="Yesil G" first="Gözde" last="Yesil">Gözde Yesil</name><name sortKey="Yuksel, Adnan" sort="Yuksel, Adnan" uniqKey="Yuksel A" first="Adnan" last="Yuksel">Adnan Yuksel</name></country><country name="Belgique"><noRegion><name sortKey="Jacquinet, Adeline" sort="Jacquinet, Adeline" uniqKey="Jacquinet A" first="Adeline" last="Jacquinet">Adeline Jacquinet</name></noRegion><name sortKey="Debray, Francois Guillaume" sort="Debray, Francois Guillaume" uniqKey="Debray F" first="François-Guillaume" last="Debray">François-Guillaume Debray</name></country><country name="France"><region name="Île-de-France"><name sortKey="Verloes, Alain" sort="Verloes, Alain" uniqKey="Verloes A" first="Alain" last="Verloes">Alain Verloes</name></region></country><country name="États-Unis"><region name="Californie"><name sortKey="Shen, Joseph" sort="Shen, Joseph" uniqKey="Shen J" first="Joseph" last="Shen">Joseph Shen</name></region><name sortKey="Taft, Ryan J" sort="Taft, Ryan J" uniqKey="Taft R" first="Ryan J" last="Taft">Ryan J. Taft</name></country><country name="Nouvelle-Zélande"><noRegion><name sortKey="Cleary, John G" sort="Cleary, John G" uniqKey="Cleary J" first="John G" last="Cleary">John G. Cleary</name></noRegion></country><country name="Royaume-Uni"><noRegion><name sortKey="Grimmond, Sean M" sort="Grimmond, Sean M" uniqKey="Grimmond S" first="Sean M" last="Grimmond">Sean M. Grimmond</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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