'Gardos Channelopathy'

A variant of hereditary Stomatocytosis with complex molecular regulation

Elisa Fermo, Anna Bogdanova, Polina Petkova-Kirova, Anna Zaninoni, Anna Paola Marcello, Asya Makhro, Pascal Hänggi, Laura Hertz, Jens Danielczok, Cristina Vercellati, Nadia Mirra, Alberto Zanella, Agostino Cortelezzi, Wilma Barcellini, Lars Kaestner, Paola Bianchi

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The Gardos channel is a Ca2+ 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 Ca2+ overload in the RBCs of both patients and hypersensitivity of Ca2+ 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.

Original languageEnglish
Article number1744
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - Dec 1 2017

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Channelopathies
Mutation
Exome
Erythroblasts
Hemolytic Anemia
Ion Transport
Ion Channels
Cell Size
Dehydration
Genes
Flow Cytometry
Hypersensitivity
Erythrocytes
Fluorescence
Pathology
Phenotype
Proteins
Hereditary Xerocytosis

ASJC Scopus subject areas

  • General

Cite this

'Gardos Channelopathy' : A variant of hereditary Stomatocytosis with complex molecular regulation. / 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.

In: Scientific Reports, Vol. 7, No. 1, 1744, 01.12.2017.

Research output: Contribution to journalArticle

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. / 'Gardos Channelopathy' : A variant of hereditary Stomatocytosis with complex molecular regulation. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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