A mutation in the Gardos channel is associated with hereditary xerocytosis
| Autor: | Jean-Pierre Desvignes, Hélène Guizouarn, David Salgado, Corinne Guitton, Henri Vinti, Christophe Béroud, Véronique Picard, Vanessa Nivaggioni, Marie Loosveld, Caroline Lacoste, Valérie Lacroze, Raphael Rapetti-Mauss, Patrick Viout, Madeleine Fénéant-Thibault, Catherine Badens, Isabelle Thuret, Elise Lombard, Nathalie Dasilva, Olivier Soriani, Monique Bernard |
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| Přispěvatelé: | Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Service d'Hématologie biologique [AP-HP Hôpital Bicêtre], Université Paris Sud-Paris Saclay-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service d'hématologie, immunologie biologiques et cytogénétique, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Institute of Developmental Biology and Cancer (IBDC), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Service de Biochimie [CHU Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service d'Hématologie pédiatrique, Hôpital de la Timone, Marseille, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire de Biochimie et de Biologie Moléculaire [Hôpital de la Conception - APHM], Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION) |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
MESH: Sequence Homology
Amino Acid [SDV]Life Sciences [q-bio] Xenopus MESH: Amino Acid Sequence medicine.disease_cause Biochemistry MESH: Recombinant Proteins MESH: Mutant Proteins MESH: Pregnancy Missense mutation MESH: Animals [SDV.BDD]Life Sciences [q-bio]/Development Biology ComputingMilieux_MISCELLANEOUS Genetics Mutation education.field_of_study MESH: Infant Newborn Hematology MESH: Infant MESH: Osmotic Fragility Hemolysis 3. Good health MESH: HEK293 Cells MESH: Models Molecular Calmodulin MESH: Pedigree MESH: Hydrops Fetalis Immunology MESH: Intermediate-Conductance Calcium-Activated Potassium Channels Biology MESH: Oocytes KCNN4 MESH: Xenopus laevis MESH: Anemia Hemolytic Congenital MESH: Patch-Clamp Techniques medicine education MESH: In Vitro Techniques MESH: Mutation Missense MESH: Erythrocytes Abnormal MESH: Molecular Sequence Data MESH: Humans Elliptocytes HEK 293 cells MESH: Child Preschool MESH: Adult Cell Biology biology.organism_classification medicine.disease Molecular biology MESH: Male biology.protein MESH: Genes Dominant MESH: Female |
| Zdroj: | Blood Blood, American Society of Hematology, 2015, 126 (11), pp.1273-80 Blood, American Society of Hematology, 2015, 126 (11), pp.1273-1280. ⟨10.1182/blood-2015-04-642496⟩ |
| ISSN: | 0006-4971 1528-0020 |
| DOI: | 10.1182/blood-2015-04-642496⟩ |
| Popis: | International audience; The Gardos channel is a Ca(2+)-sensitive, intermediate conductance, potassium selective channel expressed in several tissues including erythrocytes and pancreas. In normal erythrocytes, it is involved in cell volume modification. Here, we report the identification of a dominantly inherited mutation in the Gardos channel in 2 unrelated families and its association with chronic hemolysis and dehydrated cells, also referred to as hereditary xerocytosis (HX). The affected individuals present chronic anemia that varies in severity. Their red cells exhibit a panel of various shape abnormalities such as elliptocytes, hemighosts, schizocytes, and very rare stomatocytic cells. The missense mutation concerns a highly conserved residue among species, located in the region interacting with Calmodulin and responsible for the channel opening and the K(+) efflux. Using 2-microelectrode experiments on Xenopus oocytes and patch-clamp electrophysiology on HEK293 cells, we demonstrated that the mutated channel exhibits a higher activity and a higher Ca(2+) sensitivity compared with the wild-type (WT) channel. The mutated channel remains sensitive to inhibition suggesting that treatment of this type of HX by a specific inhibitor of the Gardos channel could be considered. The identification of a KCNN4 mutation associated with chronic hemolysis constitutes the first report of a human disease caused by a defect of the Gardos channel. |
| Databáze: | OpenAIRE |
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