DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for familial hypocalciuric hypercalcemia 1 — 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 moduleFamilial hypocalciuric hypercalcemia 1 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 familial hypocalciuric hypercalcemia 1 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
calcium sensing receptor (CASR) — CASR 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 trpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7DTV · 3.5 Å · ligand TRYPTOPHAN (TRP). Experimental structure, not a prediction.
What the evidence adds up to
Familial hypocalciuric hypercalcemia type 1 is caused by loss-of-function mutations in the calcium-sensing receptor gene on chromosome 3q21-24. A 2001 study of a 79-year-old male in Taiwan with persistent hypercalcemia and hypocalciuria found a heterozygous nonsense mutation in exon 7 at codon 648 (CGA to TGA, Arg to Ter) that predicts a markedly truncated protein. More than 30 mutations in the calcium-sensing receptor gene associated with familial hypocalciuric hypercalcemia had been described at that time. The disorder is autosomal dominant with high penetrance of lifelong benign hypercalcemia and hypocalciuria, while neonatal severe hyperparathyroidism is a life-threatening form that can cause early newborn mortality without immediate intervention.
A 2013 study identified that type 2 familial hypocalciuric hypercalcemia is due to loss-of-function mutations in GNA11, the gene encoding G-protein subunit α11, which is involved in calcium-sensing receptor signaling. In one kindred with type 2, an in-frame deletion of a conserved isoleucine (Ile200del) was found, and one of nine unrelated patients without mutations in CASR or AP2S1 had a missense mutation (Leu135Gln). In vitro expression in HEK293 cells showed that these mutations decreased the sensitivity of cells expressing calcium-sensing receptors to changes in extracellular calcium concentrations. The same study also found that gain-of-function GNA11 mutations (Arg181Gln and Phe341Leu) in two unrelated patients with hypocalcemia caused autosomal dominant hypocalcemia type 2, increasing cell sensitivity.
A 2018 review notes that familial hypocalciuric hypercalcemia usually has a benign course and patients do not require treatment, whereas neonatal severe hyperparathyroidism is severe and often requires early parathyroidectomy for young patients to survive. Recent discoveries in genetic basis and therapeutic approaches have generated interest in these rare diseases, but the review does not report any specific new treatments or clinical trial results. What remains missing are prospective studies that stratify patients by genotype, particularly to confirm that type 1, type 2, and type 3 cases truly require no intervention, and to determine whether any calcium-sensing receptor or Gα11 modulator could alter the natural history of neonatal severe hyperparathyroidism. Funding for such trials and for systematic long-term follow-up of mutation carriers is lacking.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
New England Journal of Medicine · 2013 · 404 citations · open access
Mutations Affecting G-Protein Subunit α<sub>11</sub>in Hypercalcemia and Hypocalcemia
AbstractBACKGROUND: Familial hypocalciuric hypercalcemia is a genetically heterogeneous disorder with three variants: types 1, 2, and 3. Type 1 is due to loss-of-function mutations of the calcium-sensing receptor, a guanine nucleotide-binding protein (G-protein)-coupled receptor that signals through the G-protein subunit α11 (Gα11). Type 3 is associated with adaptor-related protein complex 2, sigma 1 subunit (AP2S1) mutations, which result in altered calcium-sensing receptor endocytosis. We hypothesized that type 2 is due to mutations effecting Gα11 loss of function, since Gα11 is involved in calcium-sensing receptor signaling, and its gene (GNA11) and the type 2 locus are colocalized on chromosome 19p13.3. We also postulated that mutations effecting Gα11 gain of function, like the mutations effecting calcium-sensing receptor gain of function that cause autosomal dominant hypocalcemia type 1, may lead to hypocalcemia. METHODS: We performed GNA11 mutational analysis in a kindred with familial hypocalciuric hypercalcemia type 2 and in nine unrelated patients with familial hypocalciuric hypercalcemia who did not have mutations in the gene encoding the calcium-sensing receptor (CASR) or AP2S1. We also performed this analysis in eight unrelated patients with hypocalcemia who did not have CASR mutations. In addition, we studied the effects of GNA11 mutations on Gα11 protein structure and calcium-sensing receptor signaling in human embryonic kidney 293 (HEK293) cells. RESULTS: The kindred with familial hypocalciuric hypercalcemia type 2 had an in-frame deletion of a conserved Gα11 isoleucine (Ile200del), and one of the nine unrelated patients with familial hypocalciuric hypercalcemia had a missense GNA11 mutation (Leu135Gln). Missense GNA11 mutations (Arg181Gln and Phe341Leu) were detected in two unrelated patients with hypocalcemia; they were therefore identified as having autosomal dominant hypocalcemia type 2. All four GNA11 mutations predicted disrupted protein structures, and assessment on the basis of in vitro expression showed that familial hypocalciuric hypercalcemia type 2-associated mutations decreased the sensitivity of cells expressing calcium-sensing receptors to changes in extracellular calcium concentrations, whereas autosomal dominant hypocalcemia type 2-associated mutations increased cell sensitivity. CONCLUSIONS: Gα11 mutants with loss of function cause familial hypocalciuric hypercalcemia type 2, and Gα11 mutants with gain of function cause a clinical disorder designated as autosomal dominant hypocalcemia type 2. (Funded by the United Kingdom Medical Research Council and others.).
Frontiers of hormone research · 2018 · 23 citations
Familial Hypocalciuric Hypercalcemia and Neonatal Severe Hyperparathyroidism
AbstractFamilial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) are genetically determined variants of primary hyperparathyroidism. FHH usually has a benign course, and patients do not require treatment, whereas NSHPT is a severe disorder often requiring early parathyroidectomy for young patients to survive. Recent discoveries in the genetic basis and new findings in therapeutic approaches have led to a great interest in these rare diseases.
The Journal of Clinical Endocrinology & Metabolism · 2001 · 17 citations · open access
A Novel Mutation in the Calcium-Sensing Receptor Gene in a Chinese Subject with Persistent Hypercalcemia and Hypocalciuria1
AbstractFamilial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disorder characterized by high penetrance of relatively benign, lifelong persistent hypercalcemia and hypocalciuria. By contrast, neonatal severe hyperparathyroidism represents a life-threatening form of hypercalcemia that can cause the early newborn mortality if immediate intervention is not undertaken. Both disorders are due to inactivation mutation of the human calcium-sensing receptor (CaSR) gene on chromosome 3q21-24. Up to now, more than 30 mutations in the CaSR gene associated with FHH have been described. In this study, we analyzed one 79-yr-old male with hypocalciuric hypercalcemia without siblings or children to compare with an additional group of 50 normal Chinese subjects in Taiwan. DNA sequence analysis of the CaSR gene was performed. The result showed that the proband had a heterozygous nonsense mutation in exon 7 of the CaSR gene at codon 648 (CGA-->TGA/Arg-->Ter). This mutation, located in the COOH-terminal of the first intracellular loop of the CaSR, predicts a markedly truncated protein. We have identified a novel R648X mutation in the CaSR gene in one patient with FHH in Taiwan
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.
