Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A defect in the protein kinase-mediated phosphorylation of erythrocyte membrane proteins, previously unrecognized in stomatocytosis, was discovered in a boy with hereditary stomatocytosis and severe hemolytic anemia. The high-sodium, low-potassium erythrocytes of this patient were remarkably permeable to both sodium and potassium. The rate of ouabain-inhibitable active cation transport was more than ten times normal and was sustained by an increase of similar magnitude in glycolysis. The deformability in vitro of fresh stomatocytes was reduced and deteriorated further after a brief period of incubation with glucose. Ferrokinetic studies showed that these rigid cells were sequestered by the spleen. When stomatocytes were deprived of glucose in vitro, ATP depletion and ATPase cation pump failure rapidly ensued. Because of their permeability defect, such depleted cells rapidly became swollen and lysed. Prolonged entrapment in acidic, hypoglycemic regions of the spleen would recapitulate these unfavorable events in vivo. In this regard, splenectomy was followed by an improvement in erythrocyte survival, although evidence of continuing hemolysis was obtained.
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PMID:Hereditary stomatocytosis: membrane and metabolism studies. 117 2

A case of hereditary stomatocytosis with hemolytic anemia, increased autohemolysis, increased osmotic fragility, and shortened erythrocyte survival is reported. The erythrocytes were abnormally permeable to sodium and potassium; the sodium concentration of the erythrocytes was high, and the potassium level was low. This case was different from the first reported Japanese case of hereditary stomatocytosis of the hydrocytosis type in the Na(+)-K+ ATPase and Mg+ ATPase activity. In the first reported Japanese case, these activities were within normal limits, but in this case, they were increased. The findings indicate that membrane transport in hereditary stomatocytosis of the hydrocytosis type may vary from case to case.
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PMID:[Hereditary stomatocytosis of the hydrocytosis type: a report of one family and red cell membrane studies]. 217 Jul 5

We analyzed hemolytic reaction following vinca alkaloid administration in patients with acute lymphoblastic leukemia, blast crisis of chronic myelogenous leukemia and malignant lymphoma in the leukemic phase. During the course of chemotherapy in which vinca alkaloids were included, indirect-form dominant hyperbilirubinemia was observed in 21 of the 31 evaluable patients. In 8 patients with hyperbilirubinemia, reticulocytosis coincided with vinca alkaloid administration. Peripheral blood films showed prominent anisocytosis in 4 patients and increased stomatocytes in 10 patients. Red cell membrane studies in patients with hemolysis revealed increased sodium transport and increased activity of Na+, K+-ATPase. These findings were considered to represent the abnormal membrane "leakiness". Thus, vinca alkaloids might induce erythrocytotoxicity, which leads to acquired stomatocytosis with hemolysis in some patients.
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PMID:A transient hemolytic reaction and stomatocytosis following vinca alkaloid administration. 274 52

Erythrocyte membrane abnormalities in 3 members of a family with a hereditary haemolytic syndrome (HHS) were compared to those previously described in a family with lecithin:cholesterol acyltransferase (LCAT) deficiency. Despite similarities including an increase in membrane phosphatidylcholine, a decrease in phosphatidylethanolamine, stomatocytosis, and a marked decrease in erythrocyte osmotic fragility a number of differences were observed. These included membrane cholesterol content (increased in homozygotes with LCAT deficiency), changes in sodium and potassium content and Na+,k+-ATPase activity (the latter being increased in HHS), changes in acetylcholinesterase and sulfhydryl group latency (present in LCAT deficiency, but not in HHS) and 2,3 DPG content (decreased in HHS, normal in LCAT deficiency. Full compensation of the erythrocyte defect occurred in HHS but the homozygotes for LCAT deficiency were slightly anaemic. It is concluded that, although similar abnormalities in phospholipid composition, osmotic fragility, and erythrocyte morphology exist in these two disorders, the molecular nature of the erythrocyte membrane structural and functional changes in HHS and LCAT deficiency is clearly different.
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PMID:Study of erythrocytes in a hereditary hemolytic syndrome (HHS): comparison with erythrocytes in lecithin:cholesterol acyltransferase (LCAT) deficiency. 624 69

A rare familial case of hereditary stomatocytosis with hemolytic anemia, increased autohemolysis, increased osmotic fragility, and shortened erythrocyte survival is described. The erythrocytes were abnormally permeable to sodium and potassium. In addition, "Na-K pump" rate of the red blood cells was increased, while Na+-K+-ATPase, Mg2+-ATPase and Mg2+-Ca2+-ATPase activities were within normal limits. Splenectomy induced marked improvement of anemia.
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PMID:A family of hereditary stomatocytosis associated with normal level of Na+-K+-ATPase activity of red blood cells. 630 Dec 65

Dogs can be divided into two genetic groups (a minor HK phenotype and a major LK phenotype) based on erythrocyte monovalent cation concentrations, which are controlled by the putative hk and lk allelic genes. HK dogs retain Na,K-ATPase in their erythrocytes due to the high activity of the enzyme in their precursor cells, whereas total loss of reticulocyte Na,K-ATPase occurs in LK dogs. Here, we report that the levels of the lipid raft-associated membrane protein stomatin decrease in parallel with those of Na,K-ATPase during reticulocyte maturation due to its extrusion in exosomes. The stomatin content of HK reticulocytes is higher than that of LK reticulocytes, and remains in the erythrocytes at levels compatible with that in human erythrocytes. However, it is almost absent from LK erythrocytes with the lk/lk genotype; similar to the deficiency seen in human red cells with overhydrated stomatocytosis. LK erythrocytes from hk/lk genotype dogs show reduced, but not negligible, levels of stomatin. These results indicate that the erythrocyte stomatin level is a suitable genotypic marker for the HK/LK red cell phenotype, and suggests a functional association between stomatin and Na,K-ATPase. The absence of morphological abnormalities in the erythrocytes of stomatin-deficient LK dogs also confirms that stomatin deficiency and stomatocytic shape change are independent from each other.
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PMID:Parallel reductions in stomatin and Na,K-ATPase through the exosomal pathway during reticulocyte maturation in dogs: stomatin as a genotypic and phenotypic marker of high K(+) and low K(+) red cells. 2021 16

We report the novel, heterozygous AE1 mutation R730C associated with dominant, overhydrated, cation leak stomatocytosis and well-compensated anemia. Parallel elevations of red blood cell cation leak and ouabain-sensitive Na(+) efflux (pump activity) were apparently unaccompanied by increased erythroid cation channel-like activity, and defined ouabain-insensitive Na(+) efflux pathways of nystatin-treated cells were reduced. Epitope-tagged AE1 R730C at the Xenopus laevis oocyte surface exhibited severely reduced Cl(-) transport insensitive to rescue by glycophorin A (GPA) coexpression or by methanethiosulfonate (MTS) treatment. AE1 mutant R730K preserved Cl(-) transport activity, but R730 substitution with I, E, or H inactivated Cl(-) transport. AE1 R730C expression substantially increased endogenous oocyte Na(+)-K(+)-ATPase-mediated (86)Rb(+) influx, but ouabain-insensitive flux was minimally increased and GPA-insensitive. The reduced AE1 R730C-mediated sulfate influx did not exhibit the wild-type pattern of stimulation by acidic extracellular pH (pH(o)) and, unexpectedly, was partially rescued by exposure to sodium 2-sulfonatoethyl methanethiosulfonate (MTSES) but not to 2-aminoethyl methanethiosulfonate hydrobromide (MTSEA) or 2-(trimethylammonium)ethyl methanethiosulfonate bromide (MTSET). AE1 R730E correspondingly exhibited acid pH(o)-stimulated sulfate uptake at rates exceeding those of wild-type AE1 and AE1 R730K, whereas mutants R730I and R730H were inactive and pH(o) insensitive. MTSES-treated oocytes expressing AE1 R730C and untreated oocytes expressing AE1 R730E also exhibited unprecedented stimulation of Cl(-) influx by acid pH(o). Thus recombinant cation-leak stomatocytosis mutant AE1 R730C exhibits severely reduced anion transport unaccompanied by increased Rb(+) and Li(+) influxes. Selective rescue of acid pH(o)-stimulated sulfate uptake and conferral of acid pH(o)-stimulated Cl(-) influx, by AE1 R730E and MTSES-treated R730C, define residue R730 as critical to selectivity and regulation of anion transport by AE1.
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PMID:Functional characterization and modified rescue of novel AE1 mutation R730C associated with overhydrated cation leak stomatocytosis. 2120 59

Autosomal dominant overhydrated cation-leak stomatocytosis in humans has been associated with missense mutations in the erythroid membrane transport genes AE1, RhAG, and GLUT1. Syndromic stomatocytosis has been reported in three dog breeds, but stomatocytosis in Standard Schnauzers is usually asymptomatic, and is accompanied by minimal if any anemia. We have extended the evaluation of a cohort of schnauzers. We found that low-level stomatocytosis was accompanied by increased MCV and increased red cell Na content, and minimal or no reticulocytosis. Red cells from two affected dogs exhibited increased currents in on-cell patches measured in symmetrical NaCl solutions, but Na,K-ATPase and NKCC-mediated cation flux was minimal. Three novel coding polymorphisms found in canine RhAG cDNA and three novel polymorphisms found in canine SLC4A1 cDNA did not cosegregate with MCV or Na content. The GLUT1 cDNA sequence was normal. We conclude that unlike human overhydrated cation-leak stomatocytosis, stomatocytosis in this cohort of Standard Schnauzers is not caused by mutations in the genes encoding RhAG, SLC4A1, or GLUT1.
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PMID:Cation-leak stomatocytosis in standard schnauzers does not cosegregate with coding mutations in the RhAG, SLC4A1, or GLUT1 genes associated with human disease. 2240 15

Normal human RBCs have a very low basal permeability (leak) to cations, which is continuously corrected by the Na,K-ATPase. The leak is temperature-dependent, and this temperature dependence has been evaluated in the presence of inhibitors to exclude the activity of the Na,K-ATPase and NaK2Cl transporter. The severity of the RBC cation leak is altered in various conditions, most notably the hereditary stomatocytosis group of conditions. Pedigrees within this group have been classified into distinct phenotypes according to various factors, including the severity and temperature-dependence of the cation leak. As recent breakthroughs have provided more information regarding the molecular basis of hereditary stomatocytosis, it has become clear that these phenotypes elegantly segregate with distinct genetic backgrounds. The cryohydrocytosis phenotype, including South-east Asian Ovalocytosis, results from mutations in SLC4A1, and the very rare condition, stomatin-deficient cryohydrocytosis, is caused by mutations in SLC2A1. Mutations in RHAG cause the very leaky condition over-hydrated stomatocytosis, and mutations in ABCB6 result in familial pseudohyperkalemia. All of the above are large multi-spanning membrane proteins and the mutations may either modify the structure of these proteins, resulting in formation of a cation pore, or otherwise disrupt the membrane to allow unregulated cation movement across the membrane. More recently mutations have been found in two RBC cation channels, PIEZO1 and KCNN4, which result in dehydrated stomatocytosis. These mutations alter the activation and deactivation kinetics of these channels, leading to increased opening and allowing greater cation fluxes than in wild type.
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PMID:The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells. 2971 89