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.
journal_name
Bloodjournal_title
Bloodauthors
Rapetti-Mauss R,Lacoste C,Picard V,Guitton C,Lombard E,Loosveld M,Nivaggioni V,Dasilva N,Salgado D,Desvignes JP,Béroud C,Viout P,Bernard M,Soriani O,Vinti H,Lacroze V,Feneant-Thibault M,Thuret I,Guizouarn H,Badens Cdoi
10.1182/blood-2015-04-642496subject
Has Abstractpub_date
2015-09-10 00:00:00pages
1273-80issue
11eissn
0006-4971issn
1528-0020pii
blood-2015-04-642496journal_volume
126pub_type
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