DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for geleophysic dysplasia 2 — 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 moduleGeleophysic dysplasia 2 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 geleophysic dysplasia 2 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
fibrillin 1 (FBN1) — FBN1 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1UZK · 1.35 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Geleophysic dysplasia type 2 is an autosomal dominant disorder caused by heterozygous mutation in the fibrillin 1 (FBN1) gene, whereas type 1 is autosomal recessive and caused by mutation in ADAMTSL2. One 2021 study of three Russian female patients with acromelic dysplasias due to FBN1 mutations diagnosed one patient with geleophysic dysplasia and two with acromicric dysplasia. The most severe clinical manifestations in that series were observed in patients with mutations leading to the substitution of cysteine for arginine at position 1736 of the polypeptide chain, which may affect the transforming growth factor-beta signalling pathway. The same study reported that the c.5206T C mutation was associated with a severe phenotype of geleophysic dysplasia, while the c.5284 G A (p.Gly1762Ser) mutation led to moderate clinical manifestations of acromicric dysplasia.
A 2018 clinical update of the oldest surviving patient with geleophysic dysplasia type 1 described progressive cardiac disease and interventions over 48 years. Genetic testing in that patient revealed a previously reported missense mutation and a novel nonsense mutation in ADAMTSL2. A 2013 report of a child with two novel ADAMTSL2 mutations — c.[1934G>A] p.[Arg645His] in exon 13 and a splice-site change in intron 8 — described an aggressive clinical course with early-onset progressive cardiac valvular disease and hydrocephalus due to aqueductal stenosis as a possible new associated finding. No treatment or drug intervention was tested in any of these studies.
One abstract on ectodermal dysplasia syndrome is included but does not concern geleophysic dysplasia and provides no relevant data. No drug, repurposed or otherwise, was investigated in any of the abstracts for geleophysic dysplasia type 2 or type 1. What is missing is any clinical trial testing a pharmacological intervention, any funding for such a trial, and any stratification of patients by specific FBN1 or ADAMTSL2 mutation to guide future therapy.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
American Journal of Medical Genetics Part A · 2018 · 15 citations
Geleophysic dysplasia: 48 year clinical update with emphasis on cardiac care
AbstractGeleophysic dysplasia is a rare skeletal dysplasia often complicated by progressive cardiac disease. Information about long-term outcomes is limited. A clinical update of the oldest surviving patient described with geleophysic dysplasia type 1 is provided. Special note is made in relation to the cardiac disease and interventions. Genetic testing of ADAMTSL2 revealed a previously reported missense mutation as well as a novel nonsense mutation, which can be added to the list of causative mutations in geleophysic dysplasia.
Pediatric and Developmental Pathology · 2013 · 14 citations
Novel Mutations in Geleophysic Dysplasia Type 1
AbstractGeleophysic dysplasia (GD) is a rare genetic disorder characterized by acromelic dysplasia. Geleophysic dysplasia type 1 (MIM 231050) is autosomal recessive and is caused by homozygous or compound heterozygous mutation in the ADAMTSL2 (a disintegrin and metalloproteinase with thrombosponding repeats-like 2) gene. Geleophysic dysplasia type 2 (MIM 614185) is autosomal dominant and is caused by heterozygous mutation in the fibrillin 1 (FBN1) gene. Here, we present the clinical and histopathologic findings in a child with GD with newly identified ADAMTSL2 mutations. The 1st mutation was probably a pathogenic one, c.[1934G>A] p.[Arg645His], located in exon 13; the 2nd, in intron 8, was probably changing a splice site. While the light and electron microscopic findings were similar to those previously described, hydrocephalus due to aqueductal stenosis might be a new associated finding in these patients. This child with these 2 novel mutations also had an aggressive clinical course with early-onset progressive cardiac valvular disease.
AbstractEctodermal dysplasia (ED) syndrome comprises a large, heterogeneous group of inherited disorders that are defined by primary defects in the development of 2 or more tissues derived from the embryonic ectoderm. The tissues primarily involved are the skin and its appendages (including hair follicles, eccrine glands, sebaceous glands, nails) and teeth. The clinical features include sparse hair, abnormal or missing teeth, and an inability to sweat due to lack of sweat glands. One such case report of ectodermal dysplasia is presented here.
Pediatric Traumatology Orthopaedics and Reconstructive Surgery · 2021 · 0 citations · open access
Clinical and genetic characteristics of rare variants of acromelic skeletal dysplasias caused by mutations in the <i>FBN1</i> gene
AbstractBACKGROUND: Geleophysic dysplasia and acromicric dysplasia are rare hereditary diseases characterized by dwarfism and dysplastic skeletal features. In the literature, only a few cases of geleophysic dysplasia and acromicric dysplasia caused by mutations in the FBN1 gene are described. CLINICAL CASES: A description of the clinical and genetic characteristics of three female patients with acromelic dysplasias caused by three types of missense mutations in the FBN1 gene is presented. In two patients, on the basis of clinical manifestations and radiographic examination, acromicric dysplasia, and in one patient geleophysic dysplasia were diagnosed. It was shown that all identified mutations were localized in exons of the FBN1 gene encoding the amino acid sequence of the fifth domain, which has homology with transforming growth factor-beta. DISCUSSION: We have analyzed the clinical and genetic correlations to confirm the previously stated hypothesis about the occurrence of a severe phenotype of geleophysic dysplasia in patients with the c.5206T C mutation. This mutation is characterized by the replacement of cysteine by arginine in the position of the polypeptide chain leading to moderate clinical manifestations of acromicric dysplasia in patients with the c.5284 G A (p. Gly1762Ser). It was shown that the previously undescribed substitution c.5177G A (p.Gly1726Asp and another previously described mutation in this codon resulted in the replacement of glutamine with valine. This mutation causes the appearance of a less pronounced phenotype of AD. CONCLUSIONS: Based on the results of the examination of three Russian patients and analysis of clinical and radiographic parameters described in the literature, we reported that mutations in the FBN1 gene disrupted the amino acid sequence of the fifth like transforming growth factor-beta domain of fibrillin type 1. Importantly, these mutations are responsible for the occurrence of geleophysic dysplasia and acromicric dysplasia. However, the most severe clinical manifestations were observed in patients with mutations leading to the substitution of cysteine for arginine at the position of the polypeptide chain 1736. This may lead to affecting the transforming growth factor-beta signaling pathway.
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.
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