Functional characterization of novel ABCB6 mutations and their clinical implications in familial pseudohyperkalemia

Andolfo, Immacolata; Russo, Roberta; Manna, Francesco; Rosa, Gianluca De; Gambale, Antonella; Zouwail, Soha; Detta, Nicola; Pardo, Catia Lo; Alper, Seth L.; Brugnara, Carlo; Sharma, Alok; Franceschi, Lucia De; Iolascon, Achille

doi:10.3324/haematol.2016.142372

Cited by 29 publications

(43 citation statements)

References 32 publications

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“…Recently, the ABCB6 variants R723Q, V454A, and R276W were found in FP patients who are regular blood donors. 60,61 The blood of these patients exhibited increased potassium leakage upon storage at temperatures below 37°C. Of note, all these variants are annotated in public databases, suggesting that FP is common in the general population.…”

Section: Familial Pseudohyperkalemia and Cryohydrocytosismentioning

confidence: 99%

“…Recently, ionic flux assays on the mutations found in FP patients have demonstrated that the mutations are gain-of-function, causing an abnormal loss of potassium from cells at low temperatures. 60 These changes could lead either to a 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. Recently, the ABCB6 variants R723Q, V454A, and R276W were found in FP patients who are regular blood donors.…”

Section: Familial Pseudohyperkalemia and Cryohydrocytosismentioning

confidence: 99%

“…This interesting finding encouraged further study on the implications for neonates and infants receiving transfusion of whole blood from undiagnosed FP subjects. 60 CHC is due to mutations in the SLC4A1 gene; these are gain-of-function mutations, since they are able to transform the band 3 anion exchanger to a cation transporter (Table 1).…”

Section: Familial Pseudohyperkalemia and Cryohydrocytosismentioning

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: Familial Pseudohyperkalemia and Cryohydrocytosismentioning

confidence: 99%

Section: Familial Pseudohyperkalemia and Cryohydrocytosismentioning

confidence: 99%

Section: Familial Pseudohyperkalemia and Cryohydrocytosismentioning

confidence: 99%

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New insights on hereditary erythrocyte membrane defects

et al. 2016

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“…Our primers were designed to avoid amplification of Piezo2 , Piezo1P1 and Piezo1P2 (Ensembl Gene ID ENSG00000154864, ENSG00000233686, ENSG00000237121). 13 Missense substitution mutations in PIEZO1 (Q92508) were evaluated by PolyPhen2…”

Section: Direct Sequencing Of Piezo1 Genementioning

confidence: 99%

“…Additionally, immunofluorescence analysis demonstrated that all the mutants did not impair the plasma membrane co-localization with the cell mask plasma membrane marker ( Figure 1S). When we analyzed the activity of the channel by measurement of ouabain-and bumetanide-resistant net cation flux, as previously described, 13 we observed a greater loss of cell K+ from mutants PIEZO1-expressing cells compared to WT PIEZO1-expressing cells. Of note, the presence of the two variants E2492_L2493dup + R1864H in cis led to an increase of K+ efflux respect to each variant in heterozygous state (PIEZO-E2492_L2493dup and PIEZO1-R1864H) ( Figure 2C).…”

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confidence: 99%

PIEZO1-R1864H rare variant accounts for a genetic phenotype-modifier role in dehydrated hereditary stomatocytosis

et al. 2017

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2 Dehydrated hereditary stomatocytosis (DHS) is an autosomal dominant hereditary hemolyticanemia characterized by erythrocyte dehydration due to loss of the cation content. Affected subjects exhibit highly variable clinical presentation, ranging from absence of clinical symptoms to lethal perinatal edema. They may present severe iron overload leading to hepatic transplantation, or life threatening thromboembolic disease after splenectomy, thus making the diagnosis of this condition very tricky.1 DHS results in two different forms: (i) DHS1, the most frequent, is caused by mutations in PIEZO1, encoding a cation selective channel activated by mechanical force; (ii) DHS2due to altered KCNN4 gene, encoding a Ca2+-sensitive (Gardos) channel. [2][3][4] Particularly, PIEZO1 is a large and highly polymorphic gene. Several electrophysiology studies demonstrated that the mutations cause a gain-of-function phenotype with delayed inactivation of the channel. 5-10We herein studied seven DHS patients from two unrelated families (A-B) showing highly variable clinical expressivity and carrying the same new PIEZO1 mutation. We demonstrated that the presence of an additional de novo PIEZO1 rare missense variant in one of the two probands accounts for a more severe phenotype.Case 1 from family A (A-I1) was a 42-year-old male form UK that suffered from hemolytic anemia for over 20 years. Four out his five children also suffered from anemia ( Figure 1A). He showed gallstones and splenomegaly. On complete blood count (CBC) decreased hemoglobin (Hb) levels, increased MCV, mean corpuscular hemoglobin concentration (MCHC) and reticulocytes count were observed (Table 1). He also exhibited high levels of bilirubin and LDH, as well as increased ferritin and transferrin saturation, indicating iron overload (negative for hemochromatosis) with normal liver function. Peripheral blood smear highlighted the presence of macrocytosis, polychromasia, schistocytes and few stomatocytes.Case 2 from family B (B-II2) was a 6-year-old child from Southern Italy ( Figure 1B). At birth, he presented jaundice treated with phototherapy. At 7 months, he was admitted to hospitalization for skin and scleral jaundice. During this hospitalization, severe normocytic anemia with reticulocytosis was observed. At 3 years, he experienced severe anemia (Hb 8.3 g/dl), with reticulocytosis (181764/ml -6.12%), high platelet count (662.000/ml), signs of hemolysis (high unconjugated bilirubin and low haptoglobin levels), splenomegaly (longitudinal diameter 10.5 cm). Iron balance was normal for age (transferrin saturation 18% -ferritin 64 ng/ml). He was hospitalized several times after 3 years, requiring frequent transfusions (2/3 per year) because of hemolytic crisis.Peripheral blood smear highlighted the presence of polychromasia, schistocytes and few stomatocytes.The father B-I1 was affected too, but he showed a well-compensated anemia with normal Hb (14.6 g/dl), macrocytosis (MCV 98.2 fl), reticulocytosis (453100/ml -11.53%), and splenomegaly and a lower Hb levels (8.7±0....

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Hereditary stomatocytosis: An underdiagnosed condition

et al. 2017

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Hereditary stomatocytoses are a wide class of hemolytic anemias characterized by alterations of ionic flux with increased cation permeability that results in inappropriate shrinkage or swelling of the erythrocytes, and water lost or gained osmotically. The last few years have been crucial for new acquisitions in this field in terms of identifying new causative genes and of studying their pathogenetic mechanisms. This review summarizes the main features of erythrocyte membrane transport diseases, dividing them into forms with either isolated erythroid phenotype (nonsyndromic) or extra-hematological manifestations (syndromic), and focusing particularly on the most recent advances regarding dehydrated forms of hereditary stomatocytosis and familial pseudohyperkalemia.

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Functional characterization of novel ABCB6 mutations and their clinical implications in familial pseudohyperkalemia

Cited by 29 publications

References 32 publications

New insights on hereditary erythrocyte membrane defects

New insights on hereditary erythrocyte membrane defects

PIEZO1-R1864H rare variant accounts for a genetic phenotype-modifier role in dehydrated hereditary stomatocytosis

Hereditary stomatocytosis: An underdiagnosed condition

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