DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for acromesomelic dysplasia 3 — 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 moduleAcromesomelic dysplasia 3 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 acromesomelic dysplasia 3 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
bone morphogenetic protein receptor type 1B (BMPR1B) — BMPR1B 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 4-piperazin-1-ylphenyldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3MDY · 2.05 Å · ligand 4-[6-(4-piperazin-1-ylphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline (LDN). Experimental structure, not a prediction.
What the evidence adds up to
Acromesomelic dysplasia 3 is a skeletal disorder characterised by short stature, short hands and feet, and normal intelligence. A 2001 series of 22 patients with acromicric dysplasia, a related acromelic dysplasia, reported mean adult height of 130 cm (133 cm in males, 129 cm in females). Length was normal at birth and fell off the centiles postnatally. Other features included well developed muscles, hoarse voice, generalised joint limitation in some patients, frequent ear, tracheal, and respiratory complications, and spine abnormalities. Carpal tunnel syndrome was frequent in older patients. No major cardiac disease or orthopaedic problems occurred. The condition appeared sporadic in 16 cases, but vertical transmission in three families was consistent with autosomal dominant inheritance.
Mutations in LTBP3 cause acromicric dysplasia and geleophysic dysplasia, according to a 2016 study. A heterozygous missense mutation (exon 14: c.2087C>G: p.Ser696Cys) in LTBP3 was identified in a dominant acromicric dysplasia family. Two distinct de novo heterozygous LTBP3 mutations were found in two unrelated individuals with geleophysic dysplasia who died in early childhood from respiratory failure: a donor splice site mutation (exon 12 c.1846+5G>A) and a stop-loss mutation (exon 28: c.3912A>T: p.1304*Cysext*12). The constellation of features, including postnatal growth retardation of long bones and lung involvement, was reminiscent of the null ltbp3 mouse phenotype. LTBP3 is a novel component of the microfibrillar network involved in the acromelic dysplasia spectrum.
A 2018 study reported a novel homozygous missense variant (c.1190T > G, p.Met397Arg) in BMPR1B in a consanguineous Pakistani family with acromesomelic dysplasia Hunter-Thompson type. This was the first familial case of Hunter-Thompson type and the first report of BMPR1B underlying that subtype. The variant segregated with the disease phenotype and produced a Logarithm of odds score of 3.9. Acromesomelic dysplasia is genetically heterogeneous, caused by biallelic variants in NPR2, GDF5, and BMPR1B.
A 2020 systematic review of mutations in the FBN1-TB5 region showed that acromelic dysplasia is caused only by in-frame amino acid substitutions, while truncating mutations in that region are reported only in Marfan syndrome. Acromelic dysplasia subtypes that share symptoms with Marfan syndrome are associated with FBN1-TB5 disulfide disruptions. The type and location of mutations in the FBN1-TB5 region determine the clinical spectrum of fibrillinopathy. What is still missing is a clear understanding of how these different genetic defects converge on a common disease mechanism, and whether any existing drug could modify that mechanism. No clinical trials have been conducted for any drug in acromesomelic dysplasia 3, and no patient stratification by genotype has been attempted in a treatment context. Funding for natural history studies and for preclinical work on TGF-β pathway modulation 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.
Journal of Medical Genetics · 2016 · 63 citations
Mutations in <i>LTBP3</i> cause acromicric dysplasia and geleophysic dysplasia
AbstractBACKGROUND: Acromelic dysplasias are a group of disorders characterised by short stature, brachydactyly, limited joint extension and thickened skin and comprises acromicric dysplasia (AD), geleophysic dysplasia (GD), Myhre syndrome and Weill-Marchesani syndrome. Mutations in several genes have been identified for these disorders (including latent transforming growth factor β (TGF-β)-binding protein-2 (LTBP2), ADAMTS10, ADAMSTS17 and fibrillin-1 (FBN1) for Weill-Marchesani syndrome, ADAMTSL2 for recessive GD and FBN1 for AD and dominant GD), encoding proteins involved in the microfibrillar network. However, not all cases have mutations in these genes. METHODS: Individuals negative for mutations in known acromelic dysplasia genes underwent whole exome sequencing. RESULTS: A heterozygous missense mutation (exon 14: c.2087C>G: p.Ser696Cys) in latent transforming growth factor β (TGF-β)-binding protein-3 (LTBP3) was identified in a dominant AD family. Two distinct de novo heterozygous LTPB3 mutations were also identified in two unrelated GD individuals who had died in early childhood from respiratory failure-a donor splice site mutation (exon 12 c.1846+5G>A) and a stop-loss mutation (exon 28: c.3912A>T: p.1304*Cysext*12). CONCLUSIONS: The constellation of features in these AD and GD cases, including postnatal growth retardation of long bones and lung involvement, is reminiscent of the null ltbp3 mice phenotype. We conclude that LTBP3 is a novel component of the microfibrillar network involved in the acromelic dysplasia spectrum.
Journal of Medical Genetics · 2001 · 54 citations · open access
Acromicric dysplasia: long term outcome and evidence of autosomal dominant inheritance
AbstractAcromicric dysplasia is a rare bone dysplasia characterised by short stature, short hands and feet, normal intelligence, mild facial dysmorphism, and characteristic x ray abnormalities of the hands. Only a very small number of children with this condition have been reported so far. Here we report on a series of 22 patients including 10 boys and 12 girls with acromicric dysplasia. Length was normal at birth and height fell progressively off the centiles postnatally. The mean adult height was 130 cm (133 cm in males, 129 cm in females). The hands, feet, and limbs were short and OFC was normal. Intelligence was normal and mild dysmorphic features were noted. Other occasional features included well developed muscles, a hoarse voice, generalised joint limitation in some patients, frequent ear, tracheal, and respiratory complication, and spine abnormalities. Long term follow up showed that facial dysmorphism was less obvious in adults and that carpal tunnel syndrome was frequent in older patients. Apart from short metacarpals and phalanges, internal notch of the second metacarpal, external notch of the fifth metacarpal, and internal notch of the femoral heads, there were no major x ray abnormalities. No major complications, such as cardiac disease or major orthopaedic problems, occurred in the course of the disease. The condition appeared to be sporadic in 16 cases but the observation of vertical transmission in three families was consistent with an autosomal dominant mode of inheritance.
A novel homozygous variant in <i>BMPR1B</i> underlies acromesomelic dysplasia Hunter–Thompson type
AbstractAcromesomelic dysplasia is genetically heterogeneous group of skeletal disorders characterized by short stature and acromelia and mesomelia of limbs. Acromesomelic dysplasia segregates in an autosomal recessive pattern and is caused by biallelic sequence variants in three genes (NPR2, GDF5, and BMPR1B). A consanguineous family of Pakistani origin segregating a subtype of acromesomelic dysplasia called Hunter-Thompson was clinically and genetically evaluated. Genotyping of microsatellite markers and linkage analysis revealed a 7.78 Mb homozygous region on chromosome 4q22.3, which harbors BMPR1B. Sequence analysis of the gene revealed a novel homozygous missense variant (c.1190T > G, p.Met397Arg) that segregates with the disease phenotype within the family and produced a Logarithm of odds (LOD) score of 3.9 with the disease phenotype. This study reports on the first familial case of acromesomelic dysplasia Hunter-Thompson type. It is also the first report of BMPR1B underlying the etiology of acromesomelic dysplasia Hunter-Thompson type.
Separation in genetic pathogenesis of mutations in <scp><i>FBN1</i>‐TB5</scp> region between autosomal dominant acromelic dysplasia and Marfan syndrome
AbstractMutations in the transforming growth factor β-binding protein-like domain 5 (TB5) region of FBN1 can lead to autosomal acromelic dysplasia and Marfan syndrome, which are two diseases with apparently opposite phenotypes. We identified six patients with acromelic dysplasia carrying either the previously reported mutations c.5284G > A (p.Gly1762Ser) and c.5096A > G (p.Tyr1699Cys) or the novel mutation c.5260G > A (p.Gly1754Ser). A systematic review of patients with mutations in the FBN1-TB5 region showed that acromelic dysplasia is caused only by in-frame amino acid substitutions. In contrast, truncating mutations in the FBN1-TB5 have been reported only in Marfan syndrome. Acromelic dysplasia subtypes that share symptoms with Marfan syndrome are associated with FBN1-TB5 disulfide disruptions, which are also commonly found in Marfan syndrome. These results suggest that the type and location of mutations in the FBN1-TB5 region determine the clinical spectrum of fibrillinopathy.
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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