Mild dehydrated hereditary stomatocytosis revealed by marked hepatosiderosis

Syfuss, Pierre Yves; Ciupea, Adrian; Brahimi, S; Cynober, Thérèse; Stewart, Gordon W.; Grandchamp, Bernard; Beaumont, Carole; Tchernia, Gil; Delaunay, Jacques; Wagner, John

doi:10.1111/j.1365-2257.2006.00774.x

Cited by 27 publications

(39 citation statements)

References 23 publications

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“…Biochemical data and T2* magnetic resonance indicate the presence of hepatic iron overload, previously described as an important complication of DHSt [6,7,39]. This feature in a splenectomized patient further supports the role of dyserythropoiesis as reported for PIEZO1 mutation-associated DHSt.…”

Section: Discussionsupporting

confidence: 80%

“…The definitive diagnosis of DHSt is made by osmotic gradient ektacytometry, which shows a leftward shift of the bell-shaped curve [4,5]. Occasionally associated hepatosiderosis, beyond that expected from the mild hemolytic state, suggests a strong tendency to iron overload [6,7]. Unlike hereditary spherocytosis, in which splenectomy can be beneficial, splenectomy in DHSt is contraindicated due to increased risk of thromboembolic complications [8,9].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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“…DHS patients also exhibit a tendency toward having iron overload, regardless of the transfusion regimen or splenectomy. 35 The study of the iron metabolism in this condition is an open and interesting field of investigation, enabling the discovery of new drugs to treat the iron overload.…”

Section: Anemias Due To Altered Permeability Of Rbc Membranementioning

confidence: 99%

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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“…4,5 Occasionally, associated hepatosiderosis beyond that expected from the mild hemolytic state suggests a strong tendency to iron overload. 6 Unlike hereditary spherocytosis, in which splenectomy can be beneficial, splenectomy in DHSt is contraindicated due to increased risk of thromboembolic complications. 7,8 DHSt can present as an isolated erythroid phenotype or as associated with pseudohyperkalemia, with pre-and/or perinatal edema, or with both pseudohyperkalemia and effusions.…”

Section: Introductionmentioning

confidence: 99%