DeCure for Leydig cell hypoplasia due to complete LH resistance
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Leydig cell hypoplasia due to complete LH resistance — 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 moduleLeydig cell hypoplasia due to complete LH resistance 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 leydig cell hypoplasia due to complete lh resistance 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
luteinizing hormone/choriogonadotropin receptor (LHCGR) — LHCGR 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 2-morpholin-4-ylethanoylaminodrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7FIH · 3.2 Å · ligand 5-azanyl-N-tert-butyl-2-methylsulfanyl-4-[3-(2-morpholin-4-ylethanoylamino)phenyl]thieno[2,3-d]pyrimidine-6-carboxamide (55Z). Experimental structure, not a prediction.
What the evidence adds up to
Two novel homozygous LHCGR mutations, one in the signal peptide (p.Gln18_Leu19ins9) and one in the ectodomain (p.G71R), were identified in a 46,XY patient with severe Leydig cell hypoplasia. Both mutations greatly reduce cell surface expression of the receptor due to intracellular retention. However, the few mutant receptors that do reach the cell surface show a markedly increased intrinsic efficacy for agonist-stimulated cAMP production compared to an equally low number of wild-type receptors. This increased efficacy appears to be a general property of misfolding mutations in the ectodomain of gonadotropin receptors, but not in the serpentine domain. The finding implies that for these ectodomain mutations, very small changes in the number of mutant receptors on the cell surface can have disproportionately large effects on the clinical severity.
About 50% of patients with the full clinical phenotype of Leydig cell hypoplasia have no detectable mutation in the LHCGR coding sequence, based on molecular analysis. This suggests that other, unidentified genetic causes account for half of cases. In a separate study of 35 patients with delayed puberty in boys or primary amenorrhea in 46,XX girls, the LH receptor gene was examined for partial loss-of-function mutations that might cause a milder form of Leydig cell hypoplasia.
No clinical trial has tested any drug for Leydig cell hypoplasia. The mechanistic work on misfolding mutations raises the theoretical possibility that compounds which increase cell surface expression of mutant receptors could be beneficial, but no such compound has been identified or tested in patients. What is missing is any drug development programme, any clinical trial funding, and any patient stratification by mutation type, since the mechanism of increased efficacy only applies to ectodomain misfolding mutations and not to the many patients with no identified LHCGR mutation at all.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Molecular Endocrinology · 2015 · 7 citations · open access
Misfolding Ectodomain Mutations of the Lutropin Receptor Increase Efficacy of Hormone Stimulation
AbstractWe demonstrate 2 novel mutations of the LHCGR, each homozygous, in a 46,XY patient with severe Leydig cell hypoplasia. One is a mutation in the signal peptide (p.Gln18_Leu19ins9; referred to here as SP) that results in an alteration of the coding sequence of the N terminus of the mature mutant receptor. The other mutation (p.G71R) is also within the ectodomain. Similar to many other inactivating mutations, the cell surface expression of recombinant human LHR(SP,G71R) is greatly reduced due to intracellular retention. However, we made the unusual discovery that the intrinsic efficacy for agonist-stimulated cAMP in the reduced numbers of receptors on the cell surface was greatly increased relative to the same low number of cell surface wild-type receptor. Remarkably, this appears to be a general attribute of misfolding mutations in the ectodomains, but not serpentine domains, of the gonadotropin receptors. These findings suggest that there must be a common, shared mechanism by which disparate mutations in the ectodomain that cause misfolding and therefore reduced cell surface expression concomitantly confer increased agonist efficacy to those receptor mutants on the cell surface. Our data further suggest that, due to their increased agonist efficacy, extremely small changes in cell surface expression of misfolded ectodomain mutants cause larger than expected alterations in the cellular response to agonist. Therefore, for inactivating LHCGR mutations causing ectodomain misfolding, the numbers of cell surface mutant receptors on fetal Leydig cells of 46,XY individuals exert a more exquisite effect on the relative severity of the clinical phenotypes than already appreciated.
Oxford Medical Case Reports · 2021 · 5 citations · open access
Leydig cell hypoplasia type 1 diagnosed in early childhood with inactivating mutation in LHCGR gene
AbstractLeydig cell aplasia/hypoplasia is an autosomal recessive condition. In its complete form, these patients are 46XY but are cryptorchid and phenotypically female. Most cases reported in literature presented with in adolescence with pubertal delay. We reported a case with a predefined mutation in the LHCGR gene, presenting with swelling in the inguinal region and therefore diagnosed in early childhood. We wanted to emphasize the necessity of keeping Leydig cell hypoplasia in mind in the differential diagnosis of sexual development disorders in early childhood.
Mutations in a novel primate-specific cryptic exon of the LHCGR gene cause Leydig cell hypoplasia
AbstractLeydig cell hypoplasia (LCH), an autosomal recessive 46,XY disorder of sex differentiation, is characterized by a predominantly female phenotype with blind ending vagina, absence of breast development, primary amenorrhea due to the presence of testicular structures. It is caused by mutations in the luteinizing hormone/chorionic gonadotropin receptor (LHCGR), which either impair LH/CG binding or signal transduction. However, molecular analysis revealed that the LHCGR is apparently normal in about 50% of patients with the full clinical phenotype of LCH.
Can heterozygous intron mutations in the Luteinizing Hormone receptor gene cause delayed puberty?
AbstractLoss-of-function mutations of the LH receptor gene (Leydig cell hypoplasia) inactivate the receptor and give rise to primary amenorrhea and infertility in women and intersexual genitalia, hypospadias, micropenis and infertility in men. To evaluate if delayed puberty in boys and primary amenorrhoea in 46,XX girls can be due to partial Leydig cell hypoplasia we have studied the LH receptor gene in 35 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.
