DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Bruck syndrome — 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 moduleBruck syndrome 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 bruck syndrome 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
collagen type I alpha 2 chain (COL1A2) — COL1A2 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 8YV3 · 1.68 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Mutations in PLOD2 or FKBP10 cause Bruck syndrome, an autosomal-recessive condition that combines features of osteogenesis imperfecta with congenital joint contractures. In six consanguineous families, all probands carried mutations in one of these two genes. A homozygous frameshift mutation in the alternative exon 13a of PLOD2 was sufficient to cause Bruck syndrome, and a homozygous donor splice site mutation in PLOD2 was found in a patient with autosomal-recessive osteogenesis imperfecta without contractures. Compound heterozygous PLOD2 mutations were identified in two brothers, one with mild osteogenesis imperfecta and the other with mild Bruck syndrome, showing that PLOD2 mutations produce a phenotypic spectrum that includes both disorders.
A prenatal diagnosis in a French girl described ankle and wrist contractures at birth, with osteoporosis, long bone bowing, scoliosis, and normal collagen I. A 2022 case diagnosed prenatally by chromosomal microarray found a homozygous deletion at chromosome 3q24 involving part of PLOD2 and part of PLSCR4. Ultrasound at 12 weeks raised suspicion of short long bones, confirmed at 16 weeks, with bilateral fixed flexion of elbow, wrist, and knee joints and talipes. Mid-trimester morphology showed bilateral intrauterine fractures of humerus and femur. Late third-trimester echocardiogram revealed right heart enlargement with severe tricuspid regurgitation, pulmonary insufficiency, and a restrictive arterial duct, leading to emergency caesarean section for potential premature ductus closure. This was the first prenatal confirmation by chromosomal microarray and the second reported extra-skeletal abnormality in Bruck syndrome.
A 2023 report described siblings with Bruck syndrome type 2 caused by a new homozygous PLOD2 variant c.1885A>G (p.Thr629Ala). The 10-year-old boy had congenital flexion contractures of knee and elbow joints, few fractures, and severe kyphoscoliosis. His 13-year-old sister had no congenital contractures but had kyphoscoliosis, more severe osteoporosis, and a history of more fractures. This intrafamilial variability means that within the same genotype, the presence and severity of contractures and osteoporosis can differ markedly.
What is still missing is a systematic understanding of how PLOD2 and FKBP10 mutations produce the variable skeletal and extra-skeletal features, particularly the cardiac abnormality reported once. No clinical trial has tested any intervention. There is no prenatal or postnatal management protocol validated beyond case reports, and no patient stratification by genotype or phenotype. Funding for natural history studies and for developing standardised care guidelines is absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Human Mutation · 2012 · 99 citations
Mutations in PLOD2 cause autosomal-recessive connective tissue disorders within the Bruck syndrome-Osteogenesis imperfecta phenotypic spectrum
AbstractPLOD2 and FKBP10 are genes mutated in Bruck syndrome (BS), a condition resembling osteogenesis imperfecta (OI), but that is also typically associated with congenital joint contractures. Herein, we sought mutations in six consanguineous BS families and detected changes in either PLOD2 or FKBP10 in all cases. Two probands were found with a homozygous frameshift mutation in the alternative exon 13a of PLOD2, indicating that specific inactivation of the longer protein isoform encoded by this gene is sufficient to cause BS. In addition, by homozygosity mapping, followed by a candidate gene approach, we identified a homozygous donor splice site mutation in PLOD2 in a patient with autosomal-recessive OI (AR-OI). Screening of additional samples also revealed compound heterozygous mutations in PLOD2 in two brothers, one affected with mild AR-OI and the other with mild BS. Thus, PLOD2 in addition to causing BS is also associated with AR-OI phenotypes of variable severity.
AbstractBruck syndrome is characterized by the association of arthrogryposis and osteogenesis imperfecta. It is a distinct autosomal recessive disorder associated with normal collagen I. The main features are osteoporosis, long bone bowing and scoliosis due to vertebral deformities and congenital joint contractures. We describe a French girl who was born with ankle and wrist contractures (second antenatal discovery).
AbstractINTRODUCTION: Bruck syndrome is a rare autosomal recessive disease characterized by multiple joint contractures, bone fragility, and fractures. Two genes have been associated with Bruck syndrome, FKBP10 and PLOD2, though they are phenotypically indistinguishable. CASE PRESENTATION: We present a prenatally diagnosed case of Bruck syndrome in a young multiparous woman, with no notable personal, family or obstetric history. A 12-week ultrasound raised the suspicion of short long bones, subsequently confirmed at 16 weeks. In addition, bilateral fixed flexion of the elbow, wrist, and knee joints as well as talipes was observed. Chromosomal SNP microarray analysis (0.2 Mb) detected a homozygous deletion at chromosome 3, band q24, involving a part of PLOD2 to a part of PLSCR4. At mid-trimester morphology, bilateral intrauterine fractures of the humerus and femur were evident. In the late third trimester, a fetal echocardiogram noted enlargement of the right heart with severe tricuspid regurgitation in combination with pulmonary insufficiency and a restrictive arterial duct. The potential risk of premature closure of the ductus arteriosus near term led to delivery by emergency caesarean section. CONCLUSION: To our knowledge, this is the first case of Bruck syndrome prenatally confirmed by chromosomal microarray analysis and the second reported case with an extra-skeletal abnormality. This case highlights the importance of comprehensive fetal morphological assessment during pregnancy as diagnosis of an additional abnormality has the potential to impact both management and prognosis.
Pediatric Traumatology Orthopaedics and Reconstructive Surgery · 2023 · 2 citations · open access
Phenotypic variability in children with Bruck syndrome type 2: Clinical cases
AbstractBACKGROUND: Bruck syndrome is a rare disorder that features osteogenesis imperfecta, combined with severe congenital joint contractures often with pterygia, short stature, severe limb deformities, and progressive scoliosis. Its two forms, Bruck syndrome types 1 and 2, have similar clinical manifestations without osomal recessive inheritance and are caused by pathogenic variants of the nucleotide sequences in the FKBP10 and PLOD2 genes, respectively. CLINICAL CASES: The article demonstrates phenotypic and radiographic features as well as laboratory values of siblings with Bruck syndrome type 2 (a 10-year-old boy and a 13-year-old girl) born to healthy parents in a consanguineous marriage. The boy had congenital flexion contractures of the knee and elbow joints, few fractures, and severe kyphoscoliosis. The girl had no congenital joint contractures but had kyphoscoliosis, more severe osteoporosis, and a history of having more fractures than her younger brother. DISCUSSION: The cases demonstrated the significant phenotypic intrafamilial variability of Bruck syndrome type 2, caused by a newly identified homozygous variant c.1885AG (p.Thr629Ala) in PLOD2, which consists of varying degrees of osteoporosis, and the presence and severity of contractures. CONCLUSIONS: The description of the given clinical observation was made to draw attention to a rare pathology and expand doctors’ knowledge about the variability of clinical manifestations of Bruck syndrome. Genetic diagnostics is necessary for the timely diagnosis of Bruck syndrome, determining the prognosis and developing patient management techniques.
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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