DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for distal arthrogryposis — screening already-approved drugs against its 13-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 maps to a 13-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 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
actin alpha cardiac muscle 1 (ACTC1) — ACTC1 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 adpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9ZBL · 2.79 Å · ligand ADENOSINE-5'-DIPHOSPHATE (ADP). Experimental structure, not a prediction.
What the evidence adds up to
In a cohort of 153 cases of distal arthrogryposis type 1 (48 individuals) and type 2B (105 individuals), disease-causing mutations were found in only 56 kindreds (37 per cent overall): 14 of 48 (29 per cent) with DA1 and 42 of 105 (40 per cent) with DA2B. The mutations were distributed nearly equally across the genes TNNI2, TNNT3, TPM2, and MYH3. The same mutation in TNNI2, TNNT3, or TPM2 caused DA1 in some families and DA2B in others, and no significant differences in clinical characteristics were found by locus. The authors concluded that DA1 and DA2B should be considered phenotypic extremes of the same disorder.
A three-generation family with distal arthrogryposis and myopathy carried a heterozygous three-base in-frame deletion in TNNI2 (2,918-2,920del, skipping lysine 176). The five affected individuals had predominantly distal congenital joint contractures, mild facial involvement, and no detectable muscle weakness. The four affected adults had slightly elevated serum creatine kinase, and muscle biopsies showed myopathic changes restricted to type 2 fibres: fibre size variability, internalised nuclei, and increased interstitial connective tissue. The mutation was present in all five affected individuals and absent in 11 unaffected family members. The authors noted that distal arthrogryposis type 1 is genetically heterogeneous and that myopathy due to sarcomeric protein dysfunction may be one underlying cause.
A 14-year-old boy with contractures in the proximal joints and elevated serum creatine kinase was found to carry a heterozygous nonsense variant in TNNI1 (c.523A>T, p.K175*). Muscle biopsy showed a moth-eaten appearance in some type 1 fibres, and electron microscopy revealed Z disk streaming in type 1 fibres. The altered amino acid lies within the tropomyosin-binding site near the C-terminus, in a region homologous to the mutational hotspot of TNNI2, which is associated with distal arthrogryposis types 1 and 2B. Compared with patients carrying TNNI2 variants, this patient had a milder phenotype and proximal rather than distal contractures. The authors stated that further functional and genetic studies are required to clarify the role of TNNI1 in the disease.
What is still missing is a clear understanding of how specific mutations in these sarcomeric genes produce contractures, and why the same mutation can produce either DA1 or DA2B in different families. No large-scale, prospective natural history study has been done, and no clinical trial of any intervention has been reported. Patient stratification by genotype and muscle fibre-type involvement remains unexplored, and funding for such work is not evident from these publications.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
American Journal of Medical Genetics Part A · 2013 · 69 citations · open access
Spectrum of mutations that cause distal arthrogryposis types 1 and 2B
AbstractThe distal arthrogryposis (DA) syndromes are a group of disorders characterized by non-progressive congenital contractures of the limbs. Mutations that cause distal arthrogryposis syndromes have been reported in six genes, each of which encodes a component of the contractile apparatus of skeletal myofibers. However, these reports have usually emanated from gene discovery efforts and thus potentially bias estimates of the frequency of pathogenic mutations at each locus. We characterized the spectrum of pathogenic variants in a cohort of 153 cases of DA1 (n = 48) and DA2B (n = 105). Disease-causing mutations in 56/153 (37%) kindreds including 14/48 (29%) with DA1 and 42/105 (40%) with DA2B were distributed nearly equally across TNNI2, TNNT3, TPM2, and MYH3. In TNNI2, TNNT3, and TPM2 the same mutation caused DA1 in some families and DA2B in others. We found no significant differences among the clinical characteristics of DA by locus or between each locus and DA1 or DA2B. Collectively, the substantial overlap between phenotypic characteristics and spectrum of mutations suggests that DA1 and DA2B should be considered phenotypic extremes of the same disorder.
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.
Neurology Genetics · 2021 · 5 citations · open access
<i>TNNI1</i> Mutated in Autosomal Dominant Proximal Arthrogryposis
Abstract<h3>Objectives</h3> The main objective of this case report is to identify a gene associated with a Japanese family with autosomal dominant arthrogryposis. <h3>Methods</h3> We performed clinicopathologic diagnosis and genomic analysis using trio-based exome sequencing. <h3>Results</h3> A 14-year-old boy had contractures in the proximal joints, and the serum creatine kinase level was elevated. Muscle biopsy demonstrated a moth-eaten appearance in some type 1 fibers, and electron microscopic analysis revealed that type 1 fibers had Z disk streaming. We identified a heterozygous nonsense variant, c.523A>T (p.K175*), in <i>TNNI1</i> in the family. <h3>Discussion</h3> The altered amino acid residue is within the tropomyosin-binding site near the C-terminus, in a region homologous to the variational hotspot of Troponin I2 (TNNI2), which is associated with distal arthrogryposis type 1 and 2b. Compared with patients with <i>TNNI2</i> variants, our patient had a milder phenotype and proximal arthrogryposis. We report here a case of proximal arthrogryposis associated with a <i>TNNI1</i> nonsense variant, which expands the genetic and clinical spectrum of this disease. Further functional and genetic studies are required to clarify the role of <i>TNNI1</i> in the disease.
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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