Stomatin-deficient cryohydrocytosis results from mutations in SLC2A1: a novel form of GLUT1 deficiency syndrome

Flatt, Joanna F.; Guizouarn, Hélène; Burton, Nick; Borgèse, Franck; Tomlinson, Richard; Forsyth, Rob; Baldwin, Stephen A.; Levinson, Bari E; Quittet, Philippe; Aguilar-Martinez, Patricia; Delaunay, Jean; Stewart, Gordon W.; Bruce, Lesley J.

doi:10.1182/blood-2010-12-326645

Cited by 79 publications

(87 citation statements)

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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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Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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“…11,18,29,46 Glut1 and Glut4 are essential for normal red blood cell membrane integrity. 47,48 ICAM4 is poorly expressed in Klf1 2/2 fetal liver and in patients with CDA IV. 11,28,29 It is essential for interaction between developing erythroid cells and the central macrophage of erythroblastic islands, so it is likely to be critical for maturation of erythrocytes in vivo.…”

Section: Klf1 Regulates Genes That Encode Important Blood Groupsmentioning

confidence: 99%

KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome

Magor

Tallack

Gillinder

et al. 2015

Blood

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Key Points• Complete loss of KLF1 function is compatible with life but results in severe nonspherocytic hemolytic anemia and kernicterus.• Human KLF1 regulates most aspects of red cell biology.We describe a case of severe neonatal anemia with kernicterus caused by compound heterozygosity for null mutations in KLF1, each inherited from asymptomatic parents. One of the mutations is novel. This is the first described case of a KLF1-null human. The phenotype of severe nonspherocytic hemolytic anemia, jaundice, hepatosplenomegaly, and marked erythroblastosis is more severe than that present in congenital dyserythropoietic anemia type IV as a result of dominant mutations in the second zinc-finger of KLF1. There was a very high level of HbF expression into childhood (>70%), consistent with a key role for KLF1 in human hemoglobin switching. We performed RNA-seq on circulating erythroblasts and found that human KLF1 acts like mouse Klf1 to coordinate expression of many genes required to build a red cell including those encoding globins, cytoskeletal components, AHSP, heme synthesis enzymes, cell-cycle regulators, and blood group antigens. We identify novel KLF1 target genes including KIF23 and KIF11 which are required for proper cytokinesis. We also identify new roles for KLF1 in autophagy, global transcriptional control, and RNA splicing. We suggest loss of KLF1 should be considered in otherwise unexplained cases of severe neonatal NSHA or hydrops fetalis. (Blood. 2015;125(15):2405-2417

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“…51,52 Recently, this syndrome was associated with mutations in SLC2A1 that cause both loss of glucose transport and a cation leak. 53 …”

Section: Overhydrated Hereditary Stomatocytosismentioning

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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Stomatin-deficient cryohydrocytosis results from mutations in SLC2A1: a novel form of GLUT1 deficiency syndrome

Cited by 79 publications

References 48 publications

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

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

KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome

New insights on hereditary erythrocyte membrane defects

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