The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein

Bruce, Lesley J.; Guizouarn, Hélène; Burton, Nick; Gabillat, Nicole; Poole, Joyce; Flatt, Joanna F.; Brady, R. Leo; Borgèse, Franck; Delaunay, Jean; Stewart, Gordon W.

doi:10.1182/blood-2008-07-171140

Cited by 108 publications

(138 citation statements)

References 37 publications

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“…These changes could lead either to cation leak through the normal substrate translocation pathway of ABCB6, or to the generation of a novel constitutive or cyclic leak pathway through the protein. Alternatively, mutant ABCB6 polypeptides could activate an independent cation permeability through direct or indirect protein-protein interaction, as proposed for CHC mutations in AE1/SLC4A1 [11,15], stomatin-deficient OHSt mutations in RhAG [12,13], and suggested by the fourfold elevation of K-Cl cotransport observed in red cells of patient FP Lille (LdeF, unpublished data).…”

Section: Discussionmentioning

confidence: 93%

“…These include SLC4A1 (an ion exchange) in CHC and in atypical forms of hereditary spherostomatocytosis [10,11], RHAG (Rh-associated glycoprotein) in isolated stomatin-deficient OHSt [12,13] GLUT1 (glucose transporter 1) in echinocytosis with paroxysmal dyskinesia [14], stomatin-deficient cryohydrocytosis [15] or in CHC [16] or pseudohyperkalemia and hemolysis [17] with neurological symptoms, and PIEZO1 (mechanosensitive cation channel protein FAM38A) in DHSt [18]. These findings suggest that distinct missense mutations in various red cell membrane solute transporters or channels generate cation leak pathways either through the mutant proteins themselves or by deregulating one or more independent cation permeabilities of the red cell membrane.…”

Section: Introductionmentioning

confidence: 99%

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Missense mutations in the ABCB6 transporter cause dominant familialpseudohyperkalemia

et al. 2012

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Familial Pseudohyperkalemia (FP) is a dominant red cell trait characterized by increased serum [K 1 ] in whole blood stored at or below room temperature, without additional hematological abnormalities. Functional gene mapping and sequencing analysis of the candidate genes within the 2q35-q36 critical interval identified-in 20 affected individuals among three multigenerational FP families-two novel heterozygous missense mutations in the ABCB6 gene that cosegregated with disease phenotype. The two genomic substitutions altered two adjacent nucleotides within codon 375 of ABCB6, a porphyrin transporter that, in erythrocyte membranes, bears the Langereis blood group antigen system. The ABCB6 R375Q mutation did not alter the levels of mRNA or protein, or protein localization in mature erythrocytes or erythroid precursor cells, but it is predicted to modestly alter protein structure. ABCB6 mRNA and protein levels increase during in vitro erythroid differentiation of CD34 1 erythroid precursors and the erythroleukemia cell lines HEL and K562. These data suggest that the two missense mutations in residue 375 of the ABCB6 polypeptide found in affected individuals of families with chromosome 2-linked FP could contribute to the red cell K 1 leak characteristic of this condition. Am. J. Hematol. 88:66-72, 2013. V

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Missense mutations in the ABCB6 transporter cause dominant familialpseudohyperkalemia

et al. 2012

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“…Mutations in several genes have been shown to cause red cell cation leak disorders. These include chloride-bicarbonate exchanger SLC4A1/AE1/ Band 3 in CHC and in atypical forms of hereditary spherostomatocytosis [23,24], ammonia transporter RHAG (Rh-associated glycoprotein) in isolated stomatin-deficient OHSt [25,26], glucose transporter GLUT1 in echinocytosis with paroxysmal dyskinesia [27], stomatin-deficient CHC [28] or in CHC [29] or pseudohyperkalemia and hemolysis [30] with neurological symptoms, and PIEZO1 (mechanosensitive cation channel protein FAM38A) in DHSt [10][11][12][13]. A recent study has highlighted a novel DHSt gene, KCNN4, encoding the widely expressed KCa3.1 Gardos channel, a Ca 21 -sensitive K 1 channel of intermediate conductance [14].…”

Section: Discussionmentioning

confidence: 99%

Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis)

et al. 2015

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Dehydrated hereditary stomatocytosis (DHSt) is an autosomal dominant congenital hemolytic anemia with moderate splenomegaly and often compensated hemolysis. Affected red cells are characterized by a nonspecific cation leak of the red cell membrane, reflected in elevated sodium content, decreased potassium content, elevated MCHC and MCV, and decreased osmotic fragility. The majority of symptomatic DHSt cases reported to date have been associated with gain-of-function mutations in the mechanosensitive cation channel gene, PIEZO1. A recent study has identified two families with DHSt associated with a single mutation in the KCNN4 gene encoding the Gardos channel (KCa3.1), the erythroid Ca 21 -sensitive K 1 channel of intermediate conductance, also expressed in many other cell types. We present here, in the second report of DHSt associated with KCNN4 mutations, two previously undiagnosed DHSt families. Family NA exhibited the same de novo missense mutation as that recently described, suggesting a hot spot codon for DHSt mutations. Family WO carried a novel, inherited missense mutation in the ion transport domain of the channel. The patients' mild hemolytic anemia did not improve post-splenectomy, but splenectomy led to no serious thromboembolic events. We further characterized the expression of KCNN4 in the mutated patients and during erythroid differentiation of CD341 cells and K562 cells. We also analyzed KCNN4 expression during mouse embryonic development.

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“…In a recently published paper it is reported that point mutations in Rhassociated glycoprotein (RhAG) result in overhydrated stomatocytosis (OHSt), in which the red cells are very cation-leaky at physiological temperature. 9 RhAG is a member of the band 3 macrocomplex and there is evidence that in normal cells it may function as an ammonium transporter, and/or gas channel. 10,11 The mutations identified (Phe65Ser, Ile61Arg) occur in the predicted transmembrane span 2 of the protein and are thought to widen the pore, allowing passage of cations.…”

Section: The Hereditary Stomatocytosesmentioning

confidence: 99%

“…10,11 The mutations identified (Phe65Ser, Ile61Arg) occur in the predicted transmembrane span 2 of the protein and are thought to widen the pore, allowing passage of cations. 9 This condition is unusual, in that it is characterized by a large reduction or even absence of the membrane lipid raft protein, stomatin. The precise function of stomatin and its role in OHSt has remained a mystery.…”

Section: The Hereditary Stomatocytosesmentioning

confidence: 99%

The hereditary stomatocytoses

Flatt¹,

Bruce²

2009

Haematologica

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The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein

Cited by 108 publications

References 37 publications

Missense mutations in the ABCB6 transporter cause dominant familialpseudohyperkalemia

Missense mutations in the ABCB6 transporter cause dominant familialpseudohyperkalemia

Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis)

The hereditary stomatocytoses

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