DeCure for Lethal congenital contracture syndrome 4
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for lethal congenital contracture syndrome 4 — 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 moduleLethal congenital contracture syndrome 4 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 lethal congenital contracture syndrome 4 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
myosin binding protein C1 (MYBPC1) — MYBPC1 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 2YXM · 1.51 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Lethal congenital contracture syndrome 4 is one of a large group of conditions in which multiple joint contractures appear at birth, occurring in roughly one in 3000 births overall. Over 150 distinct genetic causes are known. The first report linking acetylcholine receptor gene mutations to arthrogryposis came in 2001, when a child with joint contractures at birth and a subsequent congenital myasthenic syndrome was found to carry two mutations in the AChR δ subunit gene: a null mutation (δ756ins2) and a missense mutation (δE59K). Expression studies showed that δE59K caused shorter-than-normal channel activations in both fetal and adult AChR, predicting fast decay of endplate currents and reduced fetal movement. That study was the first to associate AChR gene mutations with arthrogryposis multiplex congenita.
In 2022, a Chinese family with three pregnancies complicated by polyhydramnios and two liveborn infants who had limb contractures, respiratory distress, and neonatal death was investigated by whole-exome sequencing. The fetus carried a homozygous nonsense variant in CNTNAP1, c.3718C>T (p.Arg1240Ter), inherited from both parents. This variant was classified as pathogenic under ACMG criteria (PVS1+PM2+PP4) and was considered the likely cause of lethal congenital contracture syndrome type 7 in that pedigree. The finding enabled genetic counselling and prenatal diagnosis for the family.
No abstract in this set describes a drug treatment or any intervention that alters the course of lethal congenital contracture syndrome 4 or any related syndrome. All reports are limited to genetic characterisation and natural history. What is missing is any clinical trial, any repurposing candidate, any animal model testing a drug, and any funding for therapeutic development. The syndromes are rare, genetically heterogeneous, and diagnosed prenatally or at birth, so patient stratification by specific gene defect would be necessary before any intervention could be tested.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Clinical Orthopaedics and Related Research · 1985 · 143 citations
Genetic Aspects of Arthrogryposis
AbstractMultiple congenital contractures or arthrogryposis is a birth defect that occurs in approximately one in 3000 births. It can be seen in isolation or in association with other abnormalities. The etiologic and genetic basis of multiple congenital contractures is very heterogeneous. In order to understand the genetic basis and natural history of a specific case, a specific diagnosis must be made. Over 150 conditions are known in which multiple congenital contractures are a predominant sign. In this chapter, the emphasis is on a systematic differential diagnosis and consideration of empiric recurrent risk figures if a specific diagnosis cannot be reached.
Journal of Clinical Investigation · 2001 · 77 citations · open access
Acetylcholine receptor δ subunit mutations underlie a fast-channel myasthenic syndrome and arthrogryposis multiplex congenita
AbstractLimitation of movement during fetal development may lead to multiple joint contractures in the neonate, termed arthrogryposis multiplex congenita. Neuromuscular disorders are among the many different causes of reduced fetal movement. Many congenital myasthenic syndromes (CMSs) are due to mutations of the adult-specific ε subunit of the acetylcholine receptor (AChR), and, thus, functional deficits do not arise until late in gestation. However, an earlier effect on the fetus might be predicted with some defects of other AChR subunits. We studied a child who presented at birth with joint contractures and was subsequently found to have a CMS. Mutational screening revealed heteroallelic mutation within the AChR δ subunit gene, δ756ins2 and δE59K. Expression studies demonstrate that δ756ins2 is a null mutation. By contrast, both fetal and adult AChR containing δE59K have shorter than normal channel activations that predict fast decay of endplate currents. Thus, δE59K causes dysfunction of fetal as well as the adult AChR and would explain the presence of joint contractures on the basis of reduced fetal movement. This is the first report of the association of AChR gene mutations with arthrogryposis multiplex congenita. It is probable that mutations that severely disrupt function of fetal AChR will underlie additional cases.
[Analysis of CNTNAP1 gene variants in a Chinese pedigree affected with lethal congenital contracture syndrome type 7].
AbstractOBJECTIVE: To explore the genetic basis for a couple who had developed polyhydramnios during three pregnancies and given birth to two liveborns featuring limb contracture, dyspnea and neonatal death. METHODS: Whole-exome sequencing (WES) was carried out on fetal tissue and peripheral blood samples from the couple. Suspected variants were verified by Sanger sequencing. RESULTS: The fetus was found to harbor homozygous nonsense c.3718C>T (p.Arg1240Ter) variants of the CNTNAP1 gene, which were respectively inherited from its mother and father. The variant was unreported previously. According to the guidelines of the American College of Medical Genetics and Genomics, the variant was predicted to be pathogenic (PVS1+PM2+PP4). CONCLUSION: The novel homozygous nonsense variants of the CNTNAP1 gene probably underlay the lethal congenital contracture syndrome type 7 (LCCS7) in this pedigree. Above finding has enabled genetic counseling and prenatal diagnosis for the family.
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.
