DeCure for Hypothyroidism due to TSH receptor mutations
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for hypothyroidism due to TSH receptor mutations — 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 moduleHypothyroidism due to TSH receptor mutations 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 hypothyroidism due to tsh receptor mutations 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
thyroid stimulating hormone receptor (TSHR) — TSHR 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 2sdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7UTZ · 2.4 Å · ligand (2S)-3-hydroxypropane-1,2-diyl dihexadecanoate (Z41). Experimental structure, not a prediction.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Thyroid · 1998 · 9 citations
Analysis of the Promoter of the Thyrotropin Receptor Gene and the Entire Genomic Sequence of Thyroid Transcription Factor-1 in Familial Congenital Hypothyroidism due to Thyrotropin Unresponsiveness
AbstractWe previously reported that our patients with congenital primary hypothyroidism associated with thyrotropin (TSH) unresponsiveness through an autosomal recessive pattern of inheritance did not have mutations in the coding region of the TSH receptor gene. In the current study, we analyzed the promoter of the TSH receptor gene and the entire region of the thyroid transcription factor-1 (TTF-1) gene, including promoter, two exons, and one intron, because expression of the rat TSH receptor gene is reported to be stimulated by the interaction of the promoter of the TSH receptor gene with TTF-1. Screening for mutations was performed by RNase cleavage assay, and the polymerase chain reaction (PCR) products were subsequently sequenced by the automatic sequencer. In the promoter of the TSH receptor gene, a duplication of nucleotides -346 to -330 was detected in one allele, but haplotype analysis of the family demonstrated lack of linkage between the duplication and the TSH unresponsiveness. The same duplication was also observed in some normal subjects. In the TTF-1 gene, we detected a transition (guanine to adenine) in the intron at the minus four position of cryptic 3' splice site in one allele, but absence of linkage suggested that the transition was not responsible for the TSH unresponsiveness. The same transition also was found in some normal subjects. These results suggest that TSH unresponsiveness in our patients is unlikely to be caused by mutations either in the promoter of the TSH receptor gene or in the TTF-1 gene.
The Journal of Clinical Endocrinology & Metabolism · 1996 · 3 citations
Activating mutations of the thyrotropin receptor--unanswered questions
AbstractThe cloning of the TSH receptor (TSHr) in 1989-1990 was a seminal event in thyroidology. Much has been learned regarding the pathogenesis of a variety of thyroid diseases since that milestone. In recent months, it has become apparent that specific mutations of TSHr involving the transmembrane domain result in the expression of an altered receptor protein that possesses constitutive activity, i.e. increased signal transduction in the absence of its hormone ligand (l-3). These anomalous receptors are the apparent cause of some autonomously functioning thyroid nodules, where they appear as somatic mutations. More recently, germ line transmission of these mutations was found in families of patients with congenital, nonimmune hyperthyroidism (toxic thyroid hyperplasia, TTH) (4-6). In the current issue of JCEM (see page 0000), de Roux et al. describe an infant suffering from congenital, nonimmune hyperthyroidism (7). Following polymerase chain reaction (PCR) amplification of genomic DNA followed by direct sequence analysis, the authors showed that the infant expressed a TSH receptor gene containing a mutation within the second membrane-spanning segment of the transmembrane domain. Neither parent possessed the abnormal codon, indicating that the event was, in this case, a spontaneous mutation in the infant. When expressed in vitro, this mutant receptor demonstrated constitutive activity, similar to that described previously in other cases of congenital, nonimmune hyperthyroidism and autonomously functioning thyroid nodules (AFTN). The importance of the finding in this patient, other than the description of yet another mutation resulting in the phenotype, is that it is the first reported involving the second transmembrane segment, thereby expanding regions of the receptor harboring activating mutations. To date, all of the mutations found in patients with AFTN or TTH have been confined to exon 10, which codes for the entire transmembrane domain (TMD) of the receptor as well as the carboxyl terminal portion of the extracellular domain. As of the writing of this review, 13 distinct amino acid substitutions within the TMD that result in expression of a constitutively active TSH receptor and the phenotype of hyperthyroidism have been described. The locations of these mutations are well scattered across the TMD and involve the second, third, sixth, and seventh membrane-spanning segments as well as the first and second extracellular and the third intracellular loops (6, 7). Mutations within the large extracellular domain encoded by exons l-9 have also been described (8,9). However, none of these later alterations have
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.
