title: A mutation in the Gardos channel is associated with hereditary xerocytosis.
abstract: 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.
authors.affiliation: Institut de Biologie Valrose, Unité Mixte de Recherche 7277, Centre National de Recherche Scientifique, Université de Nice-Sophia Antipolis, INSERM U1091, Nice, France;
authors.forename: Raphael
authors.initials: R
authors.lastname: Rapetti-Mauss
authors.affiliation: Aix-Marseille Université, INSERM, Unité Mixte de Recherche S910, Marseille, France; Assistance Publique-Hopitaux de Marseille, Département de Génétique Médicale, Hôpital d'Enfants de la Timone, Marseille, France;
authors.forename: Caroline
authors.initials: C
authors.lastname: Lacoste
authors.affiliation: Assistance Publique-Hopitaux de Paris, Service d'Hématologie Biologique, Centre de Référence des Maladies du Globule Rouge et de l'Erythropoïèse Hôpital Bicêtre, Le Kremlin-Bicêtre, France; Laboratoire d'Hématologie, Université Paris Sud, Faculté de Pharmacie, Chatenay-Malabry, France;
authors.forename: Véronique
authors.initials: V
authors.lastname: Picard
authors.affiliation: Assistance Publique-Hopitaux de Paris, Service de Pédiatrie, Centre de Référence des Maladies du Globule Rouge et de l'Erythropoïèse Hôpital Bicêtre, Le Kremlin-Bicêtre, France;
authors.forename: Corinne
authors.initials: C
authors.lastname: Guitton
authors.affiliation: Aix-Marseille Université, INSERM, Unité Mixte de Recherche S910, Marseille, France; Assistance Publique-Hopitaux de Marseille, Laboratoire de Biochimie, Hôpital Conception, Marseille, France;
authors.forename: Elise
authors.initials: E
authors.lastname: Lombard
authors.affiliation: Assistance Publique-Hopitaux de Marseille, Laboratoire d'Hematologie, Hôpital de la Timone, Marseille, France;
authors.forename: Marie
authors.initials: M
authors.lastname: Loosveld
authors.affiliation: Assistance Publique-Hopitaux de Marseille, Laboratoire d'Hematologie, Hôpital de la Timone, Marseille, France;
authors.forename: Vanessa
authors.initials: V
authors.lastname: Nivaggioni
authors.affiliation: Aix-Marseille Université, INSERM, Unité Mixte de Recherche S910, Marseille, France;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dasilva
authors.affiliation: Aix-Marseille Université, INSERM, Unité Mixte de Recherche S910, Marseille, France;
authors.forename: David
authors.initials: D
authors.lastname: Salgado
authors.affiliation: Aix-Marseille Université, INSERM, Unité Mixte de Recherche S910, Marseille, France;
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Desvignes
authors.affiliation: Aix-Marseille Université, INSERM, Unité Mixte de Recherche S910, Marseille, France; Assistance Publique-Hopitaux de Marseille, Département de Génétique Médicale, Hôpital d'Enfants de la Timone, Marseille, France;
authors.forename: Christophe
authors.initials: C
authors.lastname: Béroud
authors.affiliation: Aix-Marseille Université, Centre National de Recherche Scientifique, Centre de Résonance Magnétique Biologique et Médicale, Unité Mixte de Recherche 7339, Marseille, France;
authors.forename: Patrick
authors.initials: P
authors.lastname: Viout
authors.affiliation: Aix-Marseille Université, Centre National de Recherche Scientifique, Centre de Résonance Magnétique Biologique et Médicale, Unité Mixte de Recherche 7339, Marseille, France;
authors.forename: Monique
authors.initials: M
authors.lastname: Bernard
authors.affiliation: Institut de Biologie Valrose, Unité Mixte de Recherche 7277, Centre National de Recherche Scientifique, Université de Nice-Sophia Antipolis, INSERM U1091, Nice, France;
authors.forename: Olivier
authors.initials: O
authors.lastname: Soriani
authors.affiliation: Service d'Hématologie Clinique, Hôpital de l'Archet, Nice, France;
authors.forename: Henri
authors.initials: H
authors.lastname: Vinti
authors.affiliation: Assistance Publique-Hopitaux de Marseille, Service de Néonatologie, Hôpital d'Enfants de la Timone, Marseille, France;
authors.forename: Valérie
authors.initials: V
authors.lastname: Lacroze
authors.affiliation: Assistance Publique-Hopitaux de Paris, Service de Biochimie, Centre de Référence des Maladies du Globule Rouge et de l'Erythropoïèse Hôpital Bicêtre, Le Kremlin-Bicêtre, France;
authors.forename: Madeleine
authors.initials: M
authors.lastname: Feneant-Thibault
authors.affiliation: Assistance Publique-Hopitaux de Marseille, Centre de Référence des Thalassémies, Service d'Hématologie Pédiatrique, Hôpital d'Enfants de la Timone, Marseille, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Thuret
authors.affiliation: Institut de Biologie Valrose, Unité Mixte de Recherche 7277, Centre National de Recherche Scientifique, Université de Nice-Sophia Antipolis, INSERM U1091, Nice, France;
authors.forename: Hélène
authors.initials: H
authors.lastname: Guizouarn
authors.affiliation: Aix-Marseille Université, INSERM, Unité Mixte de Recherche S910, Marseille, France; Assistance Publique-Hopitaux de Marseille, Département de Génétique Médicale, Hôpital d'Enfants de la Timone, Marseille, France; Assistance Publique-Hopitaux de Marseille, Laboratoire de Biochimie, Hôpital Conception, Marseille, France;
authors.forename: Catherine
authors.initials: C
authors.lastname: Badens
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000745:Anemia, Hemolytic, Congenital / Q000097:blood / Q000235:genetics*; D000818:Animals; D002675:Child, Preschool; D004913:Erythrocytes, Abnormal / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant; D057809:HEK293 Cells; D006801:Humans; D015160:Hydrops Fetalis / Q000097:blood / Q000235:genetics*; D066298:In Vitro Techniques; D007223:Infant; D007231:Infant, Newborn; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000097:blood / Q000737:chemistry / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000097:blood / Q000737:chemistry / Q000235:genetics*; D020125:Mutation, Missense; D009865:Oocytes / Q000378:metabolism; D009996:Osmotic Fragility; D018408:Patch-Clamp Techniques; D010375:Pedigree; D011247:Pregnancy; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014982:Xenopus laevis
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D050505:Mutant Proteins; D011994:Recombinant Proteins