‘Gardos Channelopathy’: a variant of hereditary Stomatocytosis with complex molecular regulation

• Published in: Scientific reports Vol. 7; no. 1; pp. 1744 - 13
• Main Authors: Fermo, Elisa, Bogdanova, Anna, Petkova-Kirova, Polina, Zaninoni, Anna, Marcello, Anna Paola, Makhro, Asya, Hänggi, Pascal, Hertz, Laura, Danielczok, Jens, Vercellati, Cristina, Mirra, Nadia, Zanella, Alberto, Cortelezzi, Agostino, Barcellini, Wilma, Kaestner, Lars, Bianchi, Paola
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.05.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 14/19; 45; 45/23; 631/80/304; 692/699/1541/13; 9/74; Adenosine Triphosphate - metabolism; Adolescent; Adult; Anemia, Hemolytic, Congenital - genetics; Calcium imaging; Calcium influx; Calcium Signaling; CD34 antigen; Cell size; Channelopathies - genetics; Channelopathy; Child; Cytoskeleton; Dehydration; Erythroblasts; Erythrocytes; Erythrocytes - metabolism; Erythroid Precursor Cells - metabolism; Family; Female; Flow cytometry; Glycolysis; Hemolytic anemia; Humanities and Social Sciences; Humans; Hydrops Fetalis - genetics; Hypersensitivity; Infant; Inheritance Patterns - genetics; Intermediate-Conductance Calcium-Activated Potassium Channels - genetics; Ion transport; Male; Models, Biological; multidisciplinary; Mutation; Mutation - genetics; Pedigree; Potassium channels (calcium-gated); Science; Science (multidisciplinary); Sodium - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-01591-w

The Gardos channel is a Ca 2+ sensitive, K + selective channel present in several tissues including RBCs, where it is involved in cell volume regulation. Recently, mutations at two different aminoacid residues in KCNN4 have been reported in patients with hereditary xerocytosis. We identified by whole exome sequencing a new family with two members affected by chronic hemolytic anemia carrying mutation R352H in the KCNN4 gene. No additional mutations in genes encoding for RBCs cytoskeletal, membrane or channel proteins were detected. We performed functional studies on patients’ RBCs to evaluate the effects of R352H mutation on the cellular properties and eventually on the clinical phenotype. Gardos channel hyperactivation was demonstrated in circulating erythrocytes and erythroblasts differentiated ex - vivo from peripheral CD34+ cells. Pathological alterations in the function of multiple ion transport systems were observed, suggesting the presence of compensatory effects ultimately preventing cellular dehydration in patient’s RBCs; moreover, flow cytometry and confocal fluorescence live-cell imaging showed Ca 2+ overload in the RBCs of both patients and hypersensitivity of Ca 2+ uptake by RBCs to swelling. Altogether these findings suggest that the ‘Gardos channelopathy’ is a complex pathology, to some extent different from the common hereditary xerocytosis.