DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for mandibuloacral dysplasia — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleMandibuloacral dysplasia maps to a 3-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 mandibuloacral dysplasia 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
zinc metallopeptidase STE24 (ZMPSTE24) — ZMPSTE24 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 pc1drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4AW6 · 3.4 Å · ligand 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE (PC1). Experimental structure, not a prediction.
What the evidence adds up to
Mandibuloacral dysplasia is a very rare disorder. A 1996 case report describes a neonatally lethal form presenting with large confluent fontanelles, sparse fine hair and eyebrows, pseudo-exophthalmos, micrognathia, bulbar digits, short clavicles, and, for the first time in this disorder, glandular hypospadias. The authors propose this represents a severe expression of mandibuloacral dysplasia.
A 2006 study identified a homozygous nucleotide substitution, 1718C>T, in exon 11 of the LMNA gene in a 44-year-old male of European descent, resulting in a serine-to-leucine change at position 573 (S573L). This mutation affects only lamin A, not lamin C. The patient had an autosomal recessive arthropathy syndrome affecting the distal femora and proximal tibia with tendinous calcifications, plus progeroid features including pinched nose, micrognathia, cataract, alopecia, generalised lipodystrophy, and sclerodermatous skin. Immunofluorescence staining of his skin fibroblasts showed occasional misshapen nuclei. The authors conclude this S573L homozygous LMNA mutation is associated with a phenotype distinct from the acro-osteolysis previously reported in mandibuloacral dysplasia caused by LMNA or ZMPSTE24 mutations.
A 2019 report describes the first case of mandibuloacral dysplasia with type B lipodystrophy (MADB) in Chile. The patient had short stature, mandibular hypoplasia, acro-osteolysis in hands, feet and clavicles, lipodystrophy, changes in skin pigments, and skin calcinosis at knees and hands. Molecular study showed two compound heterozygous variants in the ZMPSTE24 gene: c.1085dup p.(Leu362Phefs*19) and c.794A>G p.(Asn265Ser). The authors note this could help establish genotype-phenotype correlation.
What is still missing is any clinical trial data for any drug in mandibuloacral dysplasia. No treatment has been tested in a controlled study. The disorder is extremely rare, which makes patient stratification and trial design difficult, and no funding for such trials is reported.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
The Journal of Clinical Endocrinology & Metabolism · 2006 · 41 citations · open access
A Homozygous Mutation in the Lamin A/C Gene Associated with a Novel Syndrome of Arthropathy, Tendinous Calcinosis, and Progeroid Features
AbstractCONTEXT: Mutations in the lamin A/C (LMNA) gene have been reported in a wide variety of disorders, including lipodystrophies, cardiomyopathy, muscular dystrophies, neuropathy, mandibuloacral dysplasia, restrictive dermopathy, and progeria. OBJECTIVE: The objective of this study was to carry out mutational analysis of LMNA in a patient with a novel syndrome of arthropathy, tendinous calcinosis, and progeroid features. DESIGN: The study design was a descriptive case report. SETTING: The study was performed at a referral center. PATIENT: A 44-yr-old male of European descent with an autosomal recessive arthropathy syndrome affecting predominantly the distal femora and proximal tibia in the knee with tendinous calcifications was studied. He also had progeroid features, such as pinched nose and micrognathia, cataract, alopecia, generalized lipodystrophy, and sclerodermatous skin. MAIN OUTCOME MEASURES: The main outcome measures were mutational analysis of lamin A/C (LMNA) and its processing enzyme, zinc metalloproteinase (ZMPSTE24), as candidate genes. RESULTS: We found a homozygous nucleotide substitution, 1718C>T, in exon 11 of the LMNA gene, resulting in substitution of a well-conserved residue serine at position 573 with leucine (S573L). This missense mutation only affects lamin A, not lamin C, because the alternative splicing site is located in exon 10. Immunofluorescence staining of the nuclei from his skin fibroblasts showed occasional misshapen morphology. CONCLUSIONS: The S573L homozygous LMNA mutation is associated with a novel phenotype of arthropathy, tendinous calcifications, and progeroid features distinct from the acroosteolysis previously reported in patients with mandibuloacral dysplasia caused by LMNA or ZMPSTE24 mutations. Thus, arthropathy with tendinous calcifications can be added to the growing list of disorders associated with LMNA mutations.
American Journal of Medical Genetics · 1996 · 8 citations
Lethal neonatal mandibuloacral dysplasia
AbstractWe report on a case of lethal neonatal mandibuloacral dysplasia. Large confluent fontanelles, sparse fine hair and eyebrows, pseudo-exophthalmos, micrognathia, bulbar digits, and short clavicles were present. In addition, we describe for the first time the presence of glandular hypospadias in this disorder. We propose that this neonatally lethal case represents severe expression of mandibuloacral dysplasia.
American Journal of Medical Genetics Part A · 2019 · 6 citations
Mandibuloacral dysplasia with type B lipodystrophy in a patient from Chile
AbstractWe report the first case of mandibuloacral dysplasia with type B lipodystrophy (MADB) in Chile, South America. MADB is a very rare illness, characterized by short stature, mandibular hypoplasia, acro-osteolysis in hands, feet and clavicles, lipodystrophy, changes in skin pigments and skin calcinosis at knees and hands. Diagnosis was confirmed by molecular study that showed two compound heterozygous variants in ZMPSTE24 gene, c.1085dup p.(Leu362Phefs*19) and c.794A>G p.(Asn265Ser). This article could help in establishing the correlation between genotype and phenotype of this disorder, comparing with other cases previously described.
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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