A mutation in the Gardos channel is associated with hereditary xerocytosis

Rapetti-Mauss, Raphaël; Lacoste, Caroline; Picard, Véronique; Guitton, Corinne; Lombard, Elise; Loosveld, Marie; Nivaggioni, Vanessa; Dasilva, Nathalie; Salgado, David; Desvignes, Jean-Pierre; Béroud, Christophe; Viout, Patrick; Bernard, Monique; Soriani, Olivier; Vinti, H.; Lacroze, V.; Fénéant-Thibault, Madeleine; Thuret, Isabelle; Guizouarn, Hélène; Badens, Catherine

doi:10.1182/blood-2015-04-642496

Cited by 99 publications

(131 citation statements)

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“…In the last few years, remarkable progress has been made in discovering new disease genes involved in these disorders by means of unbiased genomic approaches, such as whole exome sequencing. 39,46,47,56 However, the increasing genetic heterogeneity underlines the problem of a very complex differential diagnosis. In the next generation sequencing (NGS) era, the genetic testing is going to move from few candidate genes to wider panels of genes, namely targeted (t)-NGS.…”

Section: Discussionmentioning

confidence: 99%

“…Unlike DHS1, patients affected by DHS2 show a normal pattern of ektacytometry analysis (Figure 3), 46,47 whereas they exhibit iron overload similar to that in DHS1 patients.…”

Section: Anemias Due To Altered Permeability Of Rbc Membranementioning

confidence: 99%

“…Recently, a novel gene, KCNN4, has been identified as causative of a second form of DHS, named DHS2, in six different families (Table 1). [46][47][48] The KCNN4 gene encodes the Gardos channel, a widely expressed Ca2+-dependent K+ channel of intermediate conductance that mediates the major K + conductance of erythrocytes. [46][47][48] Mutated KCNN4 channels showed a higher current compared to WT resulting from changes in the open probability, in the trafficking, and in the unitary conductance of the channel.…”

Section: Anemias Due To Altered Permeability Of Rbc Membranementioning

confidence: 99%

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New insights on hereditary erythrocyte membrane defects

et al. 2016

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© Ferrata Storti Foundationmary role in the removal of aged RBCs. In order to perform these journeys RBCs must possess and maintain a significant deformability. The main author of this property is certainly the membrane, that ensures both mechanical stability and deformability. After the first proposed model of the RBC membrane skeleton 36 years ago, 1 containing the core elements of the modern model, many additional proteins have been discovered during the intervening decades, and their structures and interactions have been defined. RBC membrane structure has been extensively covered by excellent reviews.2,3 Herein we summarize the main concepts. RBC membrane is composed by a fluid double layer of lipids in which approximately 20 major proteins and at least 850 minor ones are embedded. 4 The membrane is attached to an intracellular cytoskeleton by protein-protein and lipid-protein interactions that confer the erythrocyte shape, stability and deformability. The transmembrane proteins have mainly a transporter function. However, several of these also have a structural function, usually performed by an intracytoplasmic domain interacting with cytoskeletal proteins.The lipid bilayer acts as a barrier for the retention of cations and anions within the red cells, while it allows water molecules to pass through freely. Human erythrocytes have high intracellular K + and low intracellular Na + contents when compared with the corresponding ion concentrations in the plasma. The maintenance of this cation gradient between the cell and its environment involves a passive outward movement of K + , which is pumped back by the action of an ATP-dependent Na + /K + pump in exchange for Na+ ions. This protein belongs to a class of transmembrane proteins with a transport function (Figure 1). The third and more important component of the RBC membrane is the cytoskeleton, a protein network that laminates the inner surface of the membrane. Spectrin aand β-chains, proteins 4.1, or 4.1R, and actin are the main components of this skeleton, maintaining the biconcave shape of the RBC. These components are connected to each other in two protein complexes; ankyrin and protein 4.1 complex. The former is composed by band 3 tetramers, Rh, RhAG, CD47, glycophorin A and protein 4.2. Whereas the protein 4.1 complex is composed by band 3 dimers binding adducins a-and β-, glycophorin C, GLUT1 and stomatin (Figure 1). The ends of spectrin tetramers converge toward a protein 4.1 complex (junctional complex). Electron microscopy (EM) shows that this latter links the tail of six spectrin tetramers, forming a pseudo-hexagonal arrangement. 5Spectrin tetramers include anion transporters (band 3 or chloride/bicarbonate exchange). The capability of these transporters to form aggregates could define the half-life of RBCs, causing antibody binding and removal by the spleen. Defects that interrupt this vertical structure (spectrin-actin interaction) underlie the biochemical and molecular basis of hereditary spherocytosis (HS), whereas defects in horizo...

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Section: Discussionmentioning

confidence: 99%

“…Unlike DHS1, patients affected by DHS2 show a normal pattern of ektacytometry analysis (Figure 3), 46,47 whereas they exhibit iron overload similar to that in DHS1 patients.…”

Section: Anemias Due To Altered Permeability Of Rbc Membranementioning

confidence: 99%

Section: Anemias Due To Altered Permeability Of Rbc Membranementioning

confidence: 99%

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New insights on hereditary erythrocyte membrane defects

et al. 2016

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“…The intracellular calcium was maintained at a concentration around the threshold for KCNN4 activation (0.5 µM), 4 whilst extracellular calcium was present at 1 mM. Figure 1 and Online Supplementary Figure S3 illustrate the I/V curves for patient and control RBCs.…”

Section: A B Cmentioning

confidence: 99%

Red blood cell Gardos channel (KCNN4): the essential determinant of erythrocyte dehydration in hereditary xerocytosis

et al. 2017

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“…1,2 In 2015, a second causative gene of DHS was identified, KCNN4, encoding a Gardos channel (a Ca2+ sensitive, intermediate conductance, potassium selective channel). [4][5][6] Similarly to gain-of-function genetic variants in PIEZO1, heterozygous dominantly inherited mutations in the KCNN4 gene lead to greater activity of the channel when compared to the wild type. 4 The identification of PIEZO1 and KCNN4 variants in DHS patients strongly indicates that both genes play a critical role in normal erythrocyte deformation and in maintenance of erythrocyte volume homeostasis.…”

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confidence: 99%