DeCure for Familial hyperthyroidism due to mutations in TSH receptor
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for familial hyperthyroidism due to mutations in TSH receptor — 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 hyperthyroidism due to mutations in TSH receptor 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 hyperthyroidism due to mutations in tsh receptor 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.
What the evidence adds up to
Two siblings with a germline M463V activating mutation of the TSH receptor gene developed hereditary non-autoimmune hyperthyroidism beginning in childhood or adolescence. The 2002 report states that thyroid ablation is advocated as first-line treatment once the mutation is identified. A 2021 case describes a young adult male with a novel heterozygous TSHR variant p.Arg418Lys who had mild but progressive familial non-autoimmune autosomal dominant hyperthyroidism followed since infancy. After iodine ablation therapy his TSH remained suppressed even during hypothyroidism, suggesting central dysregulation of TSH secretion. Only around 40 families with this condition had been reported by 2021.
A 2016 report describes a family with more than one individual affected by subclinical hyperthyroidism—low TSH with normal FT3 and FT4—but no TSH receptor mutation was found. A A459 polymorphism was present in one case and three siblings. The authors conclude that a reasonable genetic cause could not be detected and suggest that epigenetic and environmental modifiers, including iodine intake, should be considered in mutation-negative families.
No drug treatment is tested or recommended in any of these abstracts. Ablative therapy (surgery or radioiodine) is the stated first-line approach, not medication. What is missing is a systematic trial comparing different ablation strategies, long-term follow-up data on central TSH dysregulation after ablation, and genetic testing protocols that can distinguish mutation-positive from mutation-negative families without relying on candidate-gene sequencing alone. Patient stratification by variant type and by the presence or absence of central dysregulation remains unaddressed.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Pediatric Endocrinology and Metabolism · 2002 · 32 citations
An Activating Mutation of the Thyrotropin Receptor Gene in Hereditary Non-Autoimmune Hyperthyroidism
AbstractThe thyroid stimulating hormone (TSH) receptor gene displays a diverse spectrum of activating and inactivating mutations. We report a germline activating mutation M463V of the TSH receptor gene in two siblings with hereditary non-autoimmune hyperthyroidism. The onset of disease in the affected members of the pedigree occurred during childhood or adolescence. The significance of diagnosing activating TSHR mutations lies in therapeutic management and genetic counseling; thyroid ablation is advocated as first line treatment.
Journal of Clinical Research in Pediatric Endocrinology · 2010 · 13 citations · open access
Sporadic Nonautoimmune Neonatal Hyperthyroidism Due to A623V Germline Mutation in the Thyrotropin Receptor Gene-Case Report
AbstractNeonatal hyperthyroidism is a rare disorder and occurs in two forms. An autoimmune form is associated with maternal Graves' disease, resulting from transplacental passage of maternal thyroid-stimulating antibodies and a nonautoimmune form is caused by gain of function mutations in the thyrotropin receptor (TSHR) gene. Thyrotoxicosis caused by germline mutations in the TSHR gene may lead to a variety of clinical consequences. To date, 55 activating mutations of the TSHR gene have been documented. Fourteen cases with sporadic activating TSHR germline mutations have been described. Here we report a male infant with nonautoimmune hyperthyroidism due to an activating germline TSHR mutation (A623V), whose clinical picture started in the newborn period with severe hyperthyroidism. His parents did not have the same mutation. This mutation had been previously detected as a somatic mutation in patients with toxic adenomas. This is the first report of a sporadic case of nonautoimmune congenital hyperthyroidism associated with A623V mutation.
Central TSH Dysregulation in a Patient with Familial Non-Autoimmune Autosomal Dominant Hyperthyroidism Due to a Novel Thyroid-Stimulating Hormone Receptor Disease-Causing Variant
AbstractBackground and Objectives. Familial non-autoimmune autosomal dominant hyperthyroidism (FNAH) is a rare cause of childhood hyperthyroidism. It is caused by the thyroid-stimulating hormone receptor (TSHR) gene variants. So far, only around 40 families with FNAH have been reported. Patients with activating TSHR variants demonstrated the same classical signs and symptoms of hyperthyroidism as seen in patients with Graves’ disease. Since 2012, ablative therapy is recommended to avoid relapses of hyperthyroidism and its consequences. Case Presentation. We presented a young adult male patient with a novel heterozygous TSHR disease-causing variant p.Arg418Lys (c.1253G>A) in the exon 10, who presented with a mild but progressive FNAH, with a follow-up since infancy. Discussion. Constantly suppressed TSH, including during the euthyreosis in childhood and hypothyreosis after iodine ablation therapy, suggested central dysregulation of the TSH secretion.
Medicine Science | International Medical Journal · 2016 · 0 citations · open access
Two siblings with familial subclinical hyperthyroidism with unknown etiology
AbstractSubclinical hyperthyroidism is defined as low or undetectable concentration of serum thyrotrophin (TSH) with normal free triiodothyronine (FT3) and free thyroxine (FT4) levels. 1). Familial subclinical hyperthyroidism is a rare entity. Activating mutations of the TSH receptor (TSH-R) gene cause genetic hyperthyroidism. Here we present a family with more than one affected individual. All family members were investigated for TSH-R mutation. No mutation was detected, while a A459 polymorphism was found in one of the cases and three other siblings. Despite the clinical and biochemical findings suggesting a TSH-R mutation, a reasonable cause could not be detected. Epigenetic and environmental modifiers, including iodine intake, should be considered in families with mutation negative, familial non auto-immune hyperthyroidism (FNAH). [Med-Science 2017; 6(1.000): 154-6]
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.
