DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for distal arthrogryposis type 2B1 — screening already-approved drugs against its 4-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleDistal arthrogryposis type 2B1 maps to a 4-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 distal arthrogryposis type 2b1 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.
What the evidence adds up to
A 2006 study of a three-generation family with distal arthrogryposis type 1 found a heterozygous three-base in-frame deletion in TNNI2 (2,918-2,920del, skipping lysine 176) in all five affected individuals but in none of the 11 unaffected family members. The five affected people had predominantly distal congenital joint contractures, mild facial involvement, and no detectable muscle weakness. The four affected adults had slightly increased creatine kinase in blood, and muscle biopsies showed myopathic changes restricted to type 2 fibres, including variability of fibre size, internalised nuclei, and increased interstitial connective tissue. The study concluded that distal arthrogryposis type 1 is genetically heterogeneous and that myopathy from sarcomeric protein dysfunction may be one underlying cause.
A 2015 study of two large Han Chinese families with distal arthrogryposis type 2 (DA2) identified two novel MYBPC1 mutations (c.1075G>A, p.E359K and c.956C>T, p.P319L), each cosegregating with the DA2 phenotype in its family but absent in population controls. The pedigrees showed autosomal dominant inheritance with incomplete penetrance and variable expressivity, including some unique overextension contractures of the lower limbs and distinctive facial features. One mutation was introduced by germline mosaicism. Both substitutions occur within the C2 immunoglobulin domain, which together with C1 and the M motif constitutes the binding site for the S2 subfragment of myosin. The authors proposed possible molecular mechanisms for DA2 myopathy associated with these substitutions.
A separate 2015 study of a three-generation Chinese pedigree with three DA-affected members used whole exome sequencing to identify a novel missense mutation in TNNI2, p.F178C, at a highly conserved position. The mutation could change the H-bond formation of a neighbouring residue, likely affecting TNNI2 protein function. A 2016 study described a female DA patient with hand and foot deformities and right-sided torticollis; exome sequencing found a novel TNNI2 mutation (c.485>A, p.Arg162Lys) in the patient and her father, who had no typical DA but hip dysplasia. The authors noted that this may explain DA2B features in the family but with variable clinical expression.
A 1985 report on 95 infants and children with arthrogryposis multiplex congenita described a regimen of early passive stretching and serial splinting. Ninety percent had contractures of all extremities; 40% had multiple congenital anomalies. Daily intensive passive stretching and serial splinting substantially increased function in this population, with surgery used only for persistent deformities. A 2017 review of lower extremity treatment in arthrogryposis multiplex congenita noted that treatment goals range from comfortable seating and shoe wear to independent ambulation, with hip and knee treatment becoming more interventional while foot deformity treatment has become much less surgical. What remains missing are prospective trials that stratify patients by specific genetic mutations, funding for genotype-phenotype correlation studies, and standardised outcome measures for the variable clinical expression seen across families.
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 · 57 citations
Passive Motion Therapy for Infants with Arthrogryposis
AbstractA comprehensive program for treatment of arthrogryposis multiplex congenita has been developed based on experiences with 95 infants and young children with arthrogrypotic deformities. The regimen emphasizes early passive stretching and serial splinting to improve joint motion. Ninety percent of the patients had contractures of all extremities; 40% had multiple congenital anomalies. Daily intensive passive stretching of joints and serial splinting have substantially increased patient function in this population. Surgical procedures have been used only in cases in which persistent deformities require correction.
A mutation in the fast skeletal muscle troponin I gene causes myopathy and distal arthrogryposis
AbstractOBJECTIVE: To describe a three-generation family with distal arthrogryposis associated with myopathy and caused by a mutation in the gene encoding for sarcomeric thin filament protein troponin I, TNNI2. METHODS: The authors performed clinical investigations and reviewed medical records. Muscle biopsy specimens were obtained for morphologic analysis. Genomic DNA was extracted from blood and analyzed for mutations in TNNI2. RESULTS: The five affected individuals had predominantly distal congenital joint contractures, mild facial involvement (mild micrognathia, narrow palpebral fissures), and no detectable muscle weakness. The four affected adults had slightly increased levels of creatine kinase in blood, and muscle biopsy specimens showed findings of myopathy with changes restricted to type 2 fibers. These included variability of muscle fiber size, internalized nuclei, and increased interstitial connective tissue. Analysis of TNNI2 encoding the troponin I isoform expressed in type 2 muscle fibers disclosed a heterozygous three-base in-frame deletion, 2,918-2,920del, skipping the highly conserved lysine at position 176. The mutation was present in all 5 affected individuals but was not identified in any of the 11 unaffected family members. CONCLUSION: Distal arthrogryposis type 1 is genetically heterogeneous, and myopathy due to sarcomeric protein dysfunction may be one underlying cause of the disease.
Two Novel Mutations in Myosin Binding Protein C Slow Causing Distal Arthrogryposis Type 2 in Two Large Han Chinese Families May Suggest Important Functional Role of Immunoglobulin Domain C2
AbstractDistal arthrogryposes (DAs) are a group of disorders that mainly involve the distal parts of the limbs and at least ten different DAs have been described to date. DAs are mostly described as autosomal dominant disorders with variable expressivity and incomplete penetrance, but recently autosomal recessive pattern was reported in distal arthrogryposis type 5D. Mutations in the contractile genes are found in about 50% of all DA patients. Of these genes, mutations in the gene encoding myosin binding protein C slow MYBPC1 were recently identified in two families with distal arthrogryposis type 1B. Here, we described two large Chinese families with autosomal dominant distal arthrogryposis type 2(DA2) with incomplete penetrance and variable expressivity. Some unique overextension contractures of the lower limbs and some distinctive facial features were present in our DA2 pedigrees. We performed follow-up DNA sequencing after linkage mapping and first identified two novel MYBPC1 mutations (c.1075G>A [p.E359K] and c.956C>T [p.P319L]) responsible for these Chinese DA2 families of which one introduced by germline mosacism. Each mutation was found to cosegregate with the DA2 phenotype in each family but not in population controls. Both substitutions occur within C2 immunoglobulin domain, which together with C1 and the M motif constitute the binding site for the S2 subfragment of myosin. Our results expand the phenotypic spectrum of MYBPC1-related arthrogryposis multiplex congenita (AMC). We also proposed the possible molecular mechanisms that may underlie the pathogenesis of DA2 myopathy associated with these two substitutions in MYBPC1.
Journal of Pediatric Orthopaedics · 2017 · 25 citations
Treatment of the Lower Extremity Contracture/Deformities
AbstractLower extremity deformities of patients with arthrogryposis multiplex congenita present a wide spectrum of severity and deformity combinations. Treatment goals range from merely ensuring comfortable seating and shoe wear, to fully independent and active ambulation, but the overarching intention is to help realize the patient’s greatest potential for independence and function. Treatment of hip and knee contractures and dislocations has become more interventional, whereas treatment of foot deformities has paradoxically become much less surgical. This article synopsizes the treatment strategies presented in September 2014 in Saint Petersburg, Russia at the second international symposium on arthrogryposis.
American Journal of Medical Genetics Part A · 2015 · 11 citations
A novel missense mutation of <i>TNNI2</i> in a Chinese family cause distal arthrogryposis type 1
AbstractThe distal arthrogryposis (DA) syndromes are a group of disorders characterized by congenital contractures of limbs. According to phenotypical characteristics, DA syndromes have been clinically classified into 10 types. Currently, at least nine disease causing genes have been identified for different types of DA. Here, we report a 3-generation Chinese pedigree with three DA affected members. We performed whole exome sequencing on two affected and one unaffected individuals of this family and successfully identified a novel missense mutation in TNNI2 as the pathogenic mutation. The TNNI2 gene encodes a subunit of the troponin complex, a contractile machinery of the muscle. The mutation p.F178C that could change the H-bond formation of a neighboring residue occurs at a highly conserved position, suggesting that this variation probably affects the TNNI2 protein function. Our study also demonstrates the power of whole exome sequencing in causal mutation identification for phenotypically variable and genetically heterogeneous disorders.
Human Genome Variation · 2016 · 8 citations · open access
Distal arthrogryposis with variable clinical expression caused by TNNI2 mutation
AbstractDistal arthrogryposis (DA) is a clinically and genetically heterogeneous disorder with multiple joint contractures. We describe a female DA patient with hand and foot deformities, and right-sided torticollis. Using exome sequencing, we identified a novel TNNI2 mutation (c.485>A, p.Arg162Lys) in the patient and her father. The father has no typical DA but hip dysplasia. This may explain the clinical features of DA2B in this family, but with variable clinical expression.
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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