DeCure for Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleDehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema maps to a 2-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
piezo type mechanosensitive ion channel component 1 (Er blood group) (PIEZO1) — PIEZO1 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet d12drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8ZU3 · 3.1 Å · ligand DODECANE (D12). Experimental structure, not a prediction.
What the evidence adds up to
Dehydrated hereditary stomatocytosis is a rare genetic defect of the erythrocyte membrane that increases permeability to sodium and potassium, causing a haemolytic anaemia with elevated mean corpuscular haemoglobin concentration and mean corpuscular volume, and decreased osmotic fragility. Some kindreds also show pseudohyperkalemia (a cold-induced rise in plasma potassium when blood is left at room temperature) or perinatal oedema. In one 1998 case report, the three features coexisted and were transmitted en bloc in a dominant fashion; transfusions did not cure the oedema, which spontaneously receded after a few months. A 1999 review noted that splenectomy, when performed, conferred a marked risk for thrombosis in adult life, stressing the importance of distinguishing these conditions from hereditary spherocytosis.
The causative genes have been identified. Familial pseudohyperkalemia is linked to mutations in ABCB6, encoding an erythrocyte ABC transporter that carries the Langereis blood group antigen. Functional characterisation of ABCB6 mutants (homozygous V454A, heterozygous R276W, and compound heterozygous R276W/R723Q) in HEK-293 cells showed greater loss of potassium or rubidium than wild-type; the R276W/R723Q combination elicited the largest efflux. The R276W variant was found in 1 of 327 random blood donors (0.3%), suggesting the trait may be common in the general population. Storage of blood from these patients leads to significantly increased potassium levels, with serious clinical implications for neonates and infants receiving large-volume transfusions of whole blood.
For dehydrated hereditary stomatocytosis, the majority of symptomatic cases have gain-of-function mutations in PIEZO1, a mechanosensitive cation channel. Whole-exome sequencing of two previously undiagnosed families identified a second causative gene, KCNN4, which encodes the Gardos channel (KCa3.1), the erythroid calcium-sensitive potassium channel of intermediate conductance. Mutations in KCNN4, like those in PIEZO1, cause a gain of function that increases potassium efflux. One study characterised a new PIEZO1 mutation — a duplication of two amino acids in the pore — found in two families with different phenotypes; a co-inherited missense variant in the family with the more severe phenotype augmented potassium efflux further.
The 2017 study recruited 97 patients from 41 unrelated families. The authors concluded that genetic tests for familial pseudohyperkalemia could be added to blood donor pre-screening, and that further study of ABCB6 function and trafficking could inform other red cell hydration disorders. They also stated that characterisation of PIEZO1 and KCNN4 mutations in dehydrated hereditary stomatocytosis would be useful for prognosis, management, follow-up, and treatment. What remains missing are prospective data on whether genetic screening of donors reduces transfusion complications, any trial of a targeted therapy (no drug is mentioned in these abstracts), and a clear stratification of patients by genotype to predict which individuals will develop perinatal oedema or post-splenectomy thrombosis.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Current Opinion in Hematology · 1999 · 58 citations
Hereditary dehydrated and overhydrated stomatocytosis: recent advances
AbstractThe hereditary stomatocytoses and allied disorders are genetic defects of the erythrocyte membrane that result in abnormal permeability to the univalent cations Na+ and K+. Although rare, these conditions reflect abnormalities in physiologic mechanisms that are of paramount interest. All cases (as defined here) show increased plasma membrane permeability to Na+ and K+ and, to a greater or lesser degree, stomatocytic morphology. Dehydrated hereditary stomatocytosis, the most common form of hereditary stomatocytosis, is more heterogeneous than previously thought and includes kindreds showing pseudohyperkalemia or perinatal edema, or both. The gene responsible for both dehydrated hereditary stomatocytosis and familial pseudohyperkalemia, a nonhemolytic variant that presents with high plasma K+ levels, has been mapped to 16q23-qter. The cause of overhydrated hereditary stomatocytosis remains elusive despite the manifest lack of the enigmatic protein stomatin in the erythrocyte membrane. In all cases where splenectomy has been performed, this procedure has conferred a marked risk for thrombosis in adult life. This finding stresses the importance of diagnostic distinction between these conditions and hereditary spherocytosis.
British Journal of Haematology · 1998 · 52 citations
A genetic syndrome associating dehydrated hereditary stomatocytosis, pseudohyperkalaemia and perinatal oedema
AbstractDehydrated hereditary stomatocytosis is a haemolytic anaemia with an underlying impairment of monovalent cation transport. It is sometimes associated with pseudohyperkalaemia (e.g. an increase of kalaemia when blood is left at room temperature) or with perinatal ascites. We report a case in which dehydrated hereditary stomatocytosis, pseudohyperkalaemia and perinatal oedema coexisted, and were transmitted en bloc in a dominant fashion. Transfusions did not cure the oedema, that spontaneously receded after a few months. We assume that the various manifestations stemmed from one single altered locus, yet to be determined.
Sub‐lethal hydrops as a manifestation of dehydrated hereditary stomatocytosis in two consecutive pregnancies
AbstractDehydrated hereditary stomatocytosis (DHS) is a rare congenital hemolytic anemia mapping to 16q23-q24. We showed recently that it is part of a pleiotropic syndrome likely to display pseudohyperkalemia and/or different forms of fetal and placental fluid collections. Here, we report a woman with DHS. She had two consecutive pregnancies associated with severe fetal hydrops. Hydrops would probably have been lethal in the absence of appropriate removal of ascites and excess amniotic fluid. In utero exchange transfusion, performed once, was useless, because anemia was not pronounced enough to be the cause of the hydrops. In both newborns, ascites resolved within a week following birth and never recurred. The association of hydrops and hemolytic anemia suggests the possibility of DHS. Symptomatic treatment of the hydrops assists survival until spontaneous resorption occurs.
Università degli Studi di Napoli Federico II · 2017 · 0 citations · open access
Molecular genetics and pathogenic mechanisms of hereditary anemias due to altered permeability of erythrocyte membrane
AbstractGenetic defects of erythrocyte transport proteins cause disorders of red blood cell volume that are characterized by abnormal permeability to the cation and, consequently, by changes in red cell hydration. Within this group of hereditary anemias we focused on familial pseudohyperkalemia and dehydrated hereditary stomatocytosis. The main aims of the project thesis are to study both the molecular genetics and the pathogenic mechanisms of these two disorders.
Isolated Familial Pseudohyperkalemia (FP) is a dominant red cell trait characterized by cold-induced ‘passive leak’ of red cell K+ into plasma. The causative gene of this condition is ABCB6, encoding an erythrocyte membrane ABC transporter protein bearing the Langereis blood group antigen system.
Dehydrated hereditary stomatocytosis (DHS) is an autosomal dominant congenital hemolytic anemia with moderate splenomegaly and often compensated hemolysis. Red cells are characterized by 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 DHS cases reported to date have been associated with gain-of-function mutations in the mechanosensitive cation channel gene, PIEZO1.
Our study started with the recruitment of 97 patients affected by both FP and DHS from 41 unrelated families of Italian and foreign countries.
Regarding familial pseudohyperkalemia, analyzing three new families, we reported the first functional characterization of ABCB6 mutants, including homozygous mutation V454A, heterozygous mutation R276W, and compound heterozygous mutations R276W and R723Q. All these mutations are annotated in public databases, suggesting that FP could be common in the general population. Indeed, we identified variant R276W in one of 327 random blood donors (0.3%). Measurement of cation flux demonstrated greater loss of K+ or Rb+ from HEK-293 cells expressing ABCB6 mutants than from cells expressing ABCB6 WT. The R276W/R723Q mutations elicited greater cellular K+ efflux than did the other mutants tested.
Regarding dehydrated hereditary stomatocytosis by whole exome sequencing analysis of two previously undiagnosed DHS families we identified the second causative gene of DHS, the KCNN4 gene, encoding the Gardos channel (KCa3.1), the erythroid Ca2+-sensitive K+ channel of intermediate conductance. We characterized the expression of KCNN4 in the mutated patients and during erythroid differentiation of hematopoietic progenitor cell CD34+ and K562 cells. We also analyzed KCNN4 expression during mouse embryonic development. Finally, we demonstrated that the mutations in KCNN4, as for PIEZO1, cause a gain of function, by increasing potassium efflux.
Moreover, by analysing the genotype of the patients here collected, we characterized a new interesting mutation in PIEZO1, that is a duplication of two aminoacids localized in the pore of the channel, found in two families with different phenotype. We further analysed the modified effect of an additional PIEZO1 missense variant carried by the family exhibiting the more severe phenotype. We found that the missense variant co-inherited with the duplication cause an augmented potassium efflux.
In conclusion, ABCB6 missense mutations in FP erythrocytes show elevated K+ efflux. The patients are present at moderate frequency in the blood donor population. Storage of blood of these patients leads to significantly increased K+ levels, with serious clinical implications for neonates and infants receiving large-volume transfusions of whole blood. Genetic tests for FP could be added to blood donor pre-screening. Further study of ABCB6 function and trafficking could be informative for the study of other pathologies of red blood cell hydration.
The identification of KCNN4 mutations in DHS patients supports recent studies that indicate it plays a critical role in normal erythrocyte deformation in the microcirculation and participates in maintenance of erythrocyte volume homeostasis. The characterization of PIEZO1 and KCNN4 mutations in DHS has contributed to the understanding of DHS pathogenesis that will be useful for the prognosis, the management, the follow-up, and the treatment of these patients.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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