DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Kniest dysplasia — 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 moduleKniest dysplasia 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 kniest 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
collagen type II alpha 1 chain (COL2A1) — COL2A1 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 p33drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5NIR · 1.74 Å · ligand 3,6,9,12,15,18-HEXAOXAICOSANE-1,20-DIOL (P33). Experimental structure, not a prediction.
What the evidence adds up to
Kniest dysplasia is a moderately severe type II collagenopathy caused by dominant mutations in the COL2A1 gene. The disorder is characterised by short trunk and limbs, kyphoscoliosis, midface hypoplasia, cleft palate, severe myopia, retinal detachment, and hearing loss. In a 1999 study of five individuals, heteroduplex analysis and sequencing identified four new dominant mutations: a 21‑bp deletion in exon 16, an 18‑bp deletion in exon 19, and 4‑bp deletions in the splice donor sites of introns 14 and 20, plus a previously described 28‑bp deletion at the exon 12‑intron 12 junction. All but one of the known mutations are located between exons 12 and 24 and cause in‑frame deletions in type II collagen, producing shorter collagen monomers. A 1994 study using SSCP found a single G‑to‑A transition in one of seven Kniest patients, substituting glycine 103 of the triple helix with aspartate; the mutation was absent in both unaffected parents, and protein microsequencing confirmed expression of the abnormal allele in cartilage. A 1998 report of a severely affected patient carrying a novel splice site mutation at position +1 of intron 22, with presumed skipping of exon 22, reviewed all published Kniest cases with identified COL2A1 mutations and noted a strong association between collagen II chain length variation and the disorder, as opposed to amino acid substitutions.
Histologic examination of cartilage in Kniest dysplasia shows an abnormal “Swiss cheese” pattern, reflecting impaired enchondral ossification of hyaline cartilage. A 2004 clinicopathologic correlation described cataract in the condition. A separate 1998 report described a 2‑year‑old girl with Burton skeletal dysplasia, a rare disorder that shows some similarities to Kniest dysplasia but is distinguished by short stature, joint stiffness, microstomia, pursed lips, platyspondyly with cervical kyphosis (no coronal clefts), and bowing of the long bones.
No clinical trial data, no survival statistics, and no response rates for any drug or intervention in Kniest dysplasia are reported in these abstracts. The literature consists entirely of case reports and mutation‑finding studies. What is missing is any prospective trial design, any patient stratification by mutation type, and any funding for therapy development.
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 · 1999 · 68 citations · open access
Small deletions in the type II collagen triple helix produce Kniest dysplasia
AbstractKniest dysplasia is a moderately severe type II collagenopathy, characterized by short trunk and limbs, kyphoscoliosis, midface hypoplasia, severe myopia, and hearing loss. Mutations in the gene that encodes type II collagen (COL2A1), the predominant protein of cartilage, have been identified in a number of individuals with Kniest dysplasia. All but two of these previously described mutations cause in-frame deletions in type II collagen, either by small deletions in the gene or splice site alterations. Furthermore, all but one of these mutations is located between exons 12 and 24 in the COL2A1 gene. We used heteroduplex analysis to identify sequence anomalies in five individuals with Kniest dysplasia. Sequencing of the index patients' genomic DNA identified four new dominant mutations in COL2A1 that result in Kniest dysplasia: a 21-bp deletion in exon 16, an 18-bp deletion in exon 19, and 4-bp deletions in the splice donor sites of introns 14 and 20. A previously described 28-bp deletion at the COL2A1 exon 12-intron 12 junction, deleting the splice donor site, was identified in the fifth case. The latter three mutations are predicted to result in exon skipping in the mRNA encoded from the mutant allele. These data suggest that Kniest dysplasia results from shorter type II collagen monomers, and support the hypothesis that alteration of a specific COL2A1 domain, which may span from exons 12 to 24, leads to the Kniest dysplasia phenotype.
A single amino acid substitution (G103D) in the type II collagen triple helix produces Kniest dysplasia
AbstractKniest dysplasia is a moderately severe chondrodysplasia phenotype that results from mutations in the gene for type II collagen, COL2A1. Characteristics of the disorder include a short trunk and extremities, mid-face hypoplasia, cleft palate, myopia, retinal detachment, and hearing loss. Recently, deletions of all or part of exon 12 have been identified in individuals with Kniest dysplasia, suggesting that mutations within this region of the protein may primarily result in the Kniest dysplasia phenotype. We used SSCP to analyze an amplified genomic DNA fragment containing exon 12 from seven individuals with Kniest dysplasia. An abnormality was identified in one patient. DNA sequence analysis demonstrated that the patient was heterozygous for a G to A transition that implied substitution of glycine103 of the triple helical domain by aspartate. The mutation was not observed in DNA from either of the clinically unaffected parents of the proband. Protein microsequencing demonstrated expression of the abnormal allele in cartilage. These data demonstrate that point mutations which result in single amino acid substitutions can produce Kniest dysplasia and further support the hypothesis that alteration of a domain, which includes the region encoded by exon 12, in the type II collagen protein leads to this disorder.
American Journal of Medical Genetics · 1998 · 12 citations
Burton skeletal dysplasia: The second case report
AbstractWe describe a 2-year-old girl with clinical and radiological findings of Burton skeletal dysplasia. This rare disorder shows some similarities to Kniest dysplasia. Short stature, joint stiffness, microstomia, and pursed lips are characteristic clinical findings. Platyspondyly with cervical kyphosis, but no coronal clefts, and bowing of the long bones are distinctive radiographic findings.
Cataract in Kniest Dysplasia: Clinicopathologic Correlation
AbstractKniest dysplasia is a variant of the spondyloepiphyseal dysplasias causedby an abnormal synthesis of collagen type II. In 1952, Kniest1 reportedthe first specific description of a variety of chondrodystrophy that he termedan atypical chondrodystrophy, which came to be knownas Kniest dysplasia.1
Fetal and Pediatric Pathology · 1998 · 1 citations
Kniest Dysplasia: Clinical, Pathologic, and Molecular Findings in a Severely Affected Patient–And Review of the Literature
AbstractKniest dysplasia is a chondrodysplasia characterized by disproportionate dwarfism and facial dysmorphic features. Enchondral ossification of hyaline cartilage is impaired, and histologic examination of cartilage shows an abnormal structure (“Swiss cheese” pattern). Dominant mutations within the gene encoding for collagen II (COL2A1), the major cartilage matrix protein, have been identified as the unifying genetic defect. Our paper describes the clinical, radiologic, pathologic, and molecular features of a patient with severe Kniest dysplasia carrying a novel splice site mutation at position + 1 of intron 22 of the COL2A1 gene with presumed skipping of exon 22. We compare our findings with all published Kniest patients with identified COL2A1 gene mutations. There is a strong association between collagen II chain length variation and Kniest dysplasia (as opposed to amino acid substitutions), suggesting a distinct pathophysiologic mechanism leading to the characteristic “hypertrophy” of cartilage; the nature of this mechanism is discussed.
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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