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Blood. 2015 Sep 10;126(11):1273-80. doi: 10.1182/blood-2015-04-642496. Epub 2015 Jul 6.

A mutation in the Gardos channel is associated with hereditary xerocytosis.

Author information

  • 1Institut de Biologie Valrose, Unité Mixte de Recherche 7277, Centre National de Recherche Scientifique, Université de Nice-Sophia Antipolis, INSERM U1091, Nice, France;
  • 2Aix-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;
  • 3Assistance 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;
  • 4Assistance 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;
  • 5Aix-Marseille Université, INSERM, Unité Mixte de Recherche S910, Marseille, France; Assistance Publique-Hopitaux de Marseille, Laboratoire de Biochimie, Hôpital Conception, Marseille, France;
  • 6Assistance Publique-Hopitaux de Marseille, Laboratoire d'Hematologie, Hôpital de la Timone, Marseille, France;
  • 7Aix-Marseille Université, INSERM, Unité Mixte de Recherche S910, Marseille, France;
  • 8Aix-Marseille Université, Centre National de Recherche Scientifique, Centre de Résonance Magnétique Biologique et Médicale, Unité Mixte de Recherche 7339, Marseille, France;
  • 9Service d'Hématologie Clinique, Hôpital de l'Archet, Nice, France;
  • 10Assistance Publique-Hopitaux de Marseille, Service de Néonatologie, Hôpital d'Enfants de la Timone, Marseille, France;
  • 11Assistance 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;
  • 12Assistance Publique-Hopitaux de Marseille, Centre de Référence des Thalassémies, Service d'Hématologie Pédiatrique, Hôpital d'Enfants de la Timone, Marseille, France.
  • 13Aix-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;

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.

© 2015 by The American Society of Hematology.

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PMID:
26148990
[PubMed - indexed for MEDLINE]
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