A mutation in the Gardos channel is associated with hereditary xerocytosis

作者：Rapetti Mauss Raphael; Lacoste Caroline; Picard Veronique; Guitton Corinne; Lombard Elise; Loosveld Marie; Nivaggioni Vanessa; Dasilva Nathalie; Salgado David; Desvignes Jean Pierre; Beroud Christophe; Viout Patrick; Bernard Monique; Soriani Olivier; Vinti Henri; Lacroze Valerie; Feneant Thibault Madeleine; Thuret Isabelle; Guizouarn Helene; Badens Catherine^*

来源：Blood, 2015, 126(11): 1273-1280.

DOI：10.1182/blood-2015-04-642496

The Gardos channel is a Ca2+-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 Xenopusoocytes and patch-clamp electrophysiology on HEK293 cells, we demonstrated that the mutated channel exhibits a higher activity and a higher Ca2+ 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.

• 出版日期2015-9-10