DeCure for Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for autosomal recessive severe congenital neutropenia due to G6PC3 deficiency — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleAutosomal recessive severe congenital neutropenia due to G6PC3 deficiency maps to a 1-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 autosomal recessive severe congenital neutropenia due to g6pc3 deficiency 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.
What the evidence adds up to
G6PC3 deficiency, also called severe congenital neutropenia type 4, is an autosomal recessive disorder caused by bi-allelic mutations in the G6PC3 gene. As of 2013, at least 57 patients had been described in the literature; a 2021 review covering five new Mexican cases and 89 previously reported patients brought the total to 94. The condition is characterised by severe congenital neutropenia, recurrent bacterial infections, intermittent thrombocytopenia, a prominent superficial venous pattern, and a high incidence of congenital cardiac defects and urogenital anomalies. The phenotypic spectrum is wide and includes maturation arrest of the myeloid lineage, normocellular bone marrow, myelokathexis, lymphopaenia, thymic hypoplasia, inflammatory bowel disease, primary pulmonary hypertension, endocrine abnormalities, growth retardation, minor facial dysmorphism, and skeletal and integument anomalies. Dursun syndrome is considered part of this extended spectrum, and isolated non-syndromic severe neutropenia can also occur. One 2013 case report described a novel homozygous p.Leu154Pro mutation accompanied by myelokathexis and hypercholesterolaemia. A 2011 report identified a novel c.765_delAG (p.S255fs) mutation in a 10-year-old boy from Ecuador, the first South American case. A 2021 report described a 12-year-old patient with the p.E65A (c.194A>C) variant who developed nephrotic-range proteinuria, amyloidosis, and end-stage renal failure during follow-up — amyloidosis had not previously been reported in G6PC3 deficiency.
The molecular pathophysiology involves reduced G6PC3 enzyme activity, endoplasmic reticulum stress, increased apoptosis of affected cells, and dysfunction of neutrophil activity. Loss of function in missense mutations likely results from decreased enzyme stability. Diagnosis is made by sequencing the G6PC3 gene; several founder mutations are known in various populations, and a possible genotype-phenotype relationship exists. Treatment with granulocyte colony-stimulating factor (G-CSF) leads to improvement in neutrophil numbers, prevents infections, and improves quality of life. Mildly affected patients can be managed with prophylactic antibiotics. Untreated G6PC3 deficiency can be fatal. Recommended routine assessments include echocardiogram, renal and pelvic ultrasound, biochemical profile, growth monitoring, and surveillance for varicose veins or venous ulcers.
The evidence base remains limited to case reports and small case series, with no controlled trials. The total number of reported patients is still under 100, and long-term outcomes on G-CSF therapy are not systematically documented. The variability in clinical presentation — syndromic versus non-syndromic, and the occurrence of rare complications such as amyloidosis — means that patient stratification is not yet possible. What is missing are prospective registries, standardised treatment protocols, and funding for natural history studies that could inform trial design.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Orphanet Journal of Rare Diseases · 2013 · 81 citations · open access
A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations
AbstractThe G6PC3 gene encodes the ubiquitously expressed glucose-6-phosphatase enzyme (G-6-Pase β or G-6-Pase 3 or G6PC3). Bi-allelic G6PC3 mutations cause a multi-system autosomal recessive disorder of G6PC3 deficiency (also called severe congenital neutropenia type 4, MIM 612541). To date, at least 57 patients with G6PC3 deficiency have been described in the literature.G6PC3 deficiency is characterized by severe congenital neutropenia, recurrent bacterial infections, intermittent thrombocytopenia in many patients, a prominent superficial venous pattern and a high incidence of congenital cardiac defects and uro-genital anomalies. The phenotypic spectrum of the condition is wide and includes rare manifestations such as maturation arrest of the myeloid lineage, a normocellular bone marrow, myelokathexis, lymphopaenia, thymic hypoplasia, inflammatory bowel disease, primary pulmonary hypertension, endocrine abnormalities, growth retardation, minor facial dysmorphism, skeletal and integument anomalies amongst others. Dursun syndrome is part of this extended spectrum. G6PC3 deficiency can also result in isolated non-syndromic severe neutropenia. G6PC3 mutations in result in reduced enzyme activity, endoplasmic reticulum stress response, increased rates of apoptosis of affected cells and dysfunction of neutrophil activity.In this review we demonstrate that loss of function in missense G6PC3 mutations likely results from decreased enzyme stability. The condition can be diagnosed by sequencing the G6PC3 gene. A number of G6PC3 founder mutations are known in various populations and a possible genotype-phenotype relationship also exists. G6PC3 deficiency should be considered as part of the differential diagnoses in any patient with unexplained congenital neutropenia.Treatment with G-CSF leads to improvement in neutrophil numbers, prevents infections and improves quality of life. Mildly affected patients can be managed with prophylactic antibiotics. Untreated G6PC3 deficiency can be fatal. Echocardiogram, renal and pelvic ultrasound scans should be performed in all cases of suspected or confirmed G6PC3 deficiency. Routine assessment should include biochemical profile, growth profile and monitoring for development of varicose veins or venous ulcers.
Journal of Pediatric Hematology/Oncology · 2011 · 15 citations
A Case of Syndromic Neutropenia and Mutation in G6PC3
AbstractBACKGROUND: A previously unrecognized syndrome with congenital neutropenia and various organ abnormalities has been described recently, caused by mutations in the gene encoding glucose-6-phosphatase, catalytic subunit 3 (G6PC3). OBSERVATION: A 10-year-old boy from Ecuador suffering from severe neutropenia and multiple nonhematopoietic abnormalities was admitted to our department. We identified a novel mutation in the G6PC3 gene (c. 765_delAG; p.S255fs). CONCLUSIONS: This is the first case of G6PC3 deficiency in a patient from South America, caused by a novel mutation in the G6PC3 gene. Our results give insights into the molecular and clinical variability of this disease.
Journal of Pediatric Hematology/Oncology · 2013 · 14 citations
A Novel G6PC3 Gene Mutation in a Patient With Severe Congenital Neutropenia
AbstractGlucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency is a newly described syndromic type of severe congenital neutropenia, associated with multiple organ abnormalities including facial, cardiac, and urogenital abnormalities, and increased visibility of superficial veins. The molecular pathophysiology of G6PC3 deficiency is associated with the disturbed glucose homeostasis, increased endoplasmic reticulum stress, and apoptosis in neutrophils. We report a new case of G6PC3 deficiency caused by a novel homozygous G6PC3 gene mutation (p.Leu154Pro). Most remarkable is that the chronic neutropenia that originated from this novel G6PC3 genetic defect is also accompanied by some other unusual manifestations in this patient: myelokathexis and hypercholesterolemia.
Journal of Pediatric Hematology/Oncology · 2021 · 5 citations
Amyloidosis in a Patient With Congenital Neutropenia Because of G6PC3 Deficiency
AbstractGlucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency is a recently identified form of congenital neutropenia associated with developmental anomalies. The severity of neutropenia and the clinical spectrum are highly variable. Aside from infectious complications and extrahematologic features, inflammatory bowel disease and autoinflammatory complications are less frequently observed manifestations. However, amyloidosis has never been reported in G6PC3 deficiency. Here, we present a 12-year-old patient with incidentally discovered neutropenia because of the p.E65A (c.194A>C) variant of the G6PC3 gene. He had recurrent aphthae and abdominal pain episodes, and developed nephrotic-range proteinuria, amyloidosis, and end-stage renal failure during follow-up.
Research Square · 2021 · 2 citations · open access
Severe Congenital Neutropenia Due To G6PC3 Deficiency Case Series of Five Patients and Literature Review
AbstractAbstract Glucose-6-phosphate catalytic subunit 3 (G6PC3) deficiency is characterized by severe congenital neutropenia with recurrent pyogenic infections, a prominent superficial venous pattern, and cardiovascular and urogenital malformations, caused by an alteration of glucose homeostasis, with increased endoplasmic reticulum stress and cell apoptosis. We describe five new cases from Mexico, and review 89 more patients reported in the past decade, to delineate the most frequent laboratory and genetic features, their treatment, and outcomes, and to expand the knowledge of syndromic and non-syndromic phenotypes in these patients.
Research Square · 2021 · 1 citations · open access
Severe congenital neutropenia due to G6PC3 deficiency. Case series of five patients and literature review
AbstractAbstract Glucose-6-phosphate catalytic subunit 3 (G6PC3) deficiency is characterized by severe congenital neutropenia with recurrent pyogenic infections, a prominent superficial venous pattern, and cardiovascular and urogenital malformations, caused by an alteration of glucose homeostasis, with increased endoplasmic reticulum stress and cell apoptosis. We describe five new cases from Mexico, and review 89 more patients reported in the past decade, to delineate the most frequent laboratory and genetic features, their treatment, and outcomes, and to expand the knowledge of syndromic and non-syndromic phenotypes in 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.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
