scholarly journals Diagnosing dehydrated hereditary stomatocytosis due to a KCNN4 Gardos channel mutation: understanding challenges through study of a multi‐generational family

eJHaem ◽  
2021 ◽  
Author(s):  
Sasha Waldstein ◽  
Sarah Arnold‐Croop ◽  
Laura Carrel ◽  
M. Elaine Eyster
Keyword(s):  
Gardos Channel ◽  
Channel Mutation

scholarly journals Gardos Channel Mutation Is Associated with Hereditary Dehydrate Stomatocytosis: a Complex Channelopathy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3333-3333
Author(s):  
Elisa Fermo ◽  
Anna Yu. Bogdanova ◽  
Polina Petkova-Kirova ◽  
Anna Zaninoni ◽  
Anna Paola Marcello ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
De Novo Mutation ◽  
Transport Systems ◽  
Diagnostic Tools ◽  
Osmotic Gradient ◽  
Single Mutation ◽  
Gardos Channel ◽  
Increased Risk ◽  
Channel Mutation

Abstract The Gardos channel (KCNN4) is a Ca2+ sensitive, intermediate conductance, K+ selective channel abundant in several tissues including red blood cells (RBC) where it is involved in cell volume regulation (Hoffman et al. 2003, Cahalan et al. 2015). Hereditary dehydrate stomatocytosis (DHSt) is characterized by mild to moderate congenital hemolytic anemia with reticulocytosis and splenomegaly associated with RBC dehydration. Affected RBC are characterized by a nonspecific cation leak, reflected in elevated Na+ content, decreased K+, elevated MCHC and MCV, and decreased osmotic fragility. The definitive diagnosis of DHSt is made by osmotic gradient ektacytometry, which shows a leftward shift of the bell-shaped curve. Heterozygous mutations associated with delayed channel inactivation have been identified for PIEZO1 (Zarychanski et al. 2012), although there are patients lacking a mutation in this gene. Differential diagnosis in hereditary stomatocytosis is important because in DHSt patients, splenectomy is contraindicated due to increased risk of thromboembolic complications. We studied a 40 year-old Italian man, affected since infancy by chronic hemolyitc anemia (Hb 7-9 g/dL, reticulocytes 10%). The unrelated parents and three siblings were healthy with normal hematologic parameters. He was occasionally transfused until splenectomy, performed at the age of 11 years. After splenectomy Hb levels maintained around 10 g/dL, thrombotic events did not occur. Increased ferritin levels (>1000 ng/ml) and moderate iron overload required chelation therapy. Peripheral blood smear showed anysopoikilocytosis with stomatocytes (13%) echinocytes (7%) schistocytes (6%) ellyptocytes (5%) spherocytes (4%). Bone marrow evaluation revealed erythroid hyperplasia with some dyserytrhopoietc changes, in particular binucleated erythroblasts. Eosin 5 maleimide (EMA) binding test was negative; despite the high number of stomatocytes in peripheral blood, the osmotic gradient ektacytometry curve was not suggestive for hereditary xerocytosis. The proband's first daughter, born at term after an uneventful pregnancy, presented with severe anemia (Hb 6.1 g/dL) requiring RBC transfusion at birth and at 4 months; at the age of 1 year she displayed a clinical pattern similar to the one of the father, with median Hb levels of 9 g/dL and no need of transfusions. To uncover the underlying etiologies, all the family members underwent whole exome sequencing. Only one candidate gene, the KCNN4 could be identified: a heterozygous missense mutation (c.1055G>A, p.R352H) was detected as a de novo mutation in the proband, and dominantly transmitted to the daughter. The mutation falling in exon 7 involved in the calmodulin binding domain was predicted to be pathogenic by in silico analysis. Sanger sequencing confirmed the presence of the mutation. Very recently (July 2015), the same mutation in the KCNN4 gene was described by other groups (Rapetti-Mauss et al. 2015; Andolfo et al. 2015). In heterologous expression systems it could be shown that the Ca2+ sensitivity of the mutated Gardos channel was increased. We performed single cell experiments, including patch-clamp recordings in RBCs and precursor cells, Ca2+ fluorescence imaging as well as tracer flux experiments in RBCs of the above described patients and healthy controls to get a mechanistic link between the Gardos channel mutation and the cellular symptoms. Despite the presence of a single mutation in Gardos channel alone, pathological alterations in function of multiple ion transport systems were revealed during these studies. Our findings together with recent reports (Rapetti-Mauss et al. 2015; Andolfo et al. 2015; Glogowska et al. 2015) suggest that the prevalence of mutations in the Gardos channel is higher than previously thought. Therefore it is important to understand the mechanisms implicated by the mutation and to develop reliable diagnostic tools and treatment strategies. Disclosures No relevant conflicts of interest to declare.

scholarly journals Role of Calcium in Phosphatidylserine Externalisation in Red Blood Cells from Sickle Cell Patients

Anemia ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Erwin Weiss ◽  
David Charles Rees ◽  
John Stanley Gibson
Keyword(s):  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Phosphatidylserine Exposure ◽  
Channel Inhibition ◽  
Cation Conductance ◽  
Gardos Channel ◽  
Cation Permeability

Phosphatidylserine exposure occurs in red blood cells (RBCs) from sickle cell disease (SCD) patients and is increased by deoxygenation. The mechanisms responsible remain unclear. RBCs from SCD patients also have elevated cation permeability, and, in particular, a deoxygenation-induced cation conductance which mediates entry, providing an obvious link with phosphatidylserine exposure. The role of was investigated using FITC-labelled annexin. Results confirmed high phosphatidylserine exposure in RBCs from SCD patients increasing upon deoxygenation. When deoxygenated, phosphatidylserine exposure was further elevated as extracellular [] was increased. This effect was inhibited by dipyridamole, intracellular chelation, and Gardos channel inhibition. Phosphatidylserine exposure was reduced in high saline. levels required to elicit phosphatidylserine exposure were in the low micromolar range. Findings are consistent with entry through the deoxygenation-induced pathway (), activating the Gardos channel. [] required for phosphatidylserine scrambling are in the range achievablein vivo.

scholarly journals A cardiac sodium channel mutation identified in Brugada syndrome associated with atrial standstill

2004 ◽  
Vol 255 (1) ◽  
pp. 137-142 ◽  
Author(s):  
N. Takehara ◽  
N. Makita ◽  
J. Kawabe ◽  
N. Sato ◽  
Y. Kawamura ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Brugada Syndrome ◽  
Cardiac Sodium Channel ◽  
Channel Mutation ◽  
Sodium Channel Mutation

scholarly journals Exaggerated cation leak from oxygenated sickle red blood cells during deformation: evidence for a unique leak pathway

Blood ◽  
1992 ◽  
Vol 80 (9) ◽  
pp. 2374-2378
Author(s):  
T Sugihara ◽  
RP Hebbel
Keyword(s):  
Shear Stress ◽  
Lipid Hydroperoxide ◽  
Viscous Medium ◽  
Permeability Barrier ◽  
Biochemical Basis ◽  
Rbc Membrane ◽  
Gardos Channel ◽  
Ambient Oxygen ◽  
Applied Shear Stress ◽  
Leak Pathway

An abnormal susceptibility of the sickle red blood cell (RBC) membrane to deformation could compromise its permeability barrier function and contribute to the exuberant cation leakiness occurring during the sickling phenomenon. We examined this hypothesis by subjecting RBCs at ambient oxygen tension to elliptical deformation, applying shear stress in a viscous medium under physiologic conditions. Compared with normal and high-reticulocyte control RBCs, sickle RBCs manifest an exaggerated K leak response to deformation. This leak is fully reversible, is both Cl and Ca independent, and at pHe 7.4 is fully balanced so that Kefflux equals Nainflux. This abnormal susceptibility is also evident in that the K leak in response to deformation occurs at an applied shear stress of only 141 dyne/cm2 for sickle RBCs, as compared to 204 dyne/cm2 for normal RBCs. Fresh sickle RBC membranes contain elevated amounts of lipid hydroperoxide, the presence of which is believed to provide the biochemical basis for enhanced deformation susceptibility. When examined at pHe 6.8, oxygenated sickle RBCs acquire an additional, unbalanced (Kefflux > Nainflux) component to the K leak increment specifically ascribable to deformation. Studies with inhibitors suggest that this additional component is not caused by a known leak pathway (eg, either K:Cl cotransport or the Gardos channel). This abnormal susceptibility of the sickle membrane to development of cation leakiness during deformation probably contributes to the exuberant cation leak taking place during RBC sickling.

scholarly journals A Single Na + Channel Mutation Causing Both Long-QT and Brugada Syndromes

1999 ◽  
Vol 85 (12) ◽  
pp. 1206-1213 ◽  
Author(s):  
Connie Bezzina ◽  
Marieke W. Veldkamp ◽  
Maarten P. van den Berg ◽  
Alex V. Postma ◽  
Martin B. Rook ◽  
...  
Keyword(s):  
Na Channel ◽  
Long Qt ◽  
Channel Mutation

scholarly journals A cardiac sodium channel mutation associated with epinephrine‐induced marked QT‐prolongation

2020 ◽  
Vol 31 (8) ◽  
pp. 2116-2117
Author(s):  
Mohamad N. El Moheb ◽  
Marwan M. Refaat
Keyword(s):  
Sodium Channel ◽  
Qt Prolongation ◽  
Cardiac Sodium Channel ◽  
Channel Mutation ◽  
Sodium Channel Mutation
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