DeCure for Multiple epiphyseal dysplasia due to collagen 9 anomaly
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for multiple epiphyseal dysplasia due to collagen 9 anomaly — 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 moduleMultiple epiphyseal dysplasia due to collagen 9 anomaly 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
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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 multiple epiphyseal dysplasia due to collagen 9 anomaly 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 IX alpha 1 chain (COL9A1) — COL9A1 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 2UUR · 1.8 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
In a 1989 study of spondyloepiphyseal dysplasia, a family was found to carry a heterozygous single-exon deletion in the type II collagen gene COL2A1. Nearly 90 percent of assembled type II collagen homotrimers in affected members were predicted to contain one or more procollagen subunits with an interstitial deletion of 36 amino acids in the triple helical domain. That disorder is distinct from multiple epiphyseal dysplasia, and a 1993 study of a five-generation family with autosomal dominant multiple epiphyseal dysplasia explicitly excluded mutations in COL2A1 and in the three genes encoding type VI collagen by linkage analysis.
Multiple epiphyseal dysplasia is genetically heterogeneous. A 1998 study of a large family with 54 affected individuals found a mutation in COL9A2. Every affected person had knee involvement; elbow, ankle, wrist, hand, and feet joints were also affected. Shoulder or hip involvement was never seen after adolescence. Height ranged from short to normal, spinal involvement was never seen, penetrance was complete, but expression was highly variable. A 2010 study identified COL9A2 mutations in two families with multiple epiphyseal dysplasia who also had osteochondritis dissecans and mild myopathy, extending the range of gene mutations that can cause myopathy in this disease. Splicing mutations in all three type IX collagen genes (COL9A1, COL9A2, COL9A3) are restricted to specific exons encoding an equivalent region of the COL3 domain.
A 2025 case report describes a ten-year-old Southeast Asian girl whose initial symptoms led to an extensive workup for myopathy that yielded no conclusion. The diagnosis of multiple epiphyseal dysplasia was made by genetic testing. No family history was present, consistent with variable penetrance of autosomal dominant mutations. No treatment or intervention is described in any of these abstracts. What remains missing is any clinical trial testing a drug for this condition, any systematic patient stratification by specific gene mutation, and any funded effort to develop a therapy for the type IX collagen forms of multiple epiphyseal dysplasia.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Science · 1989 · 248 citations
Identification of the Molecular Defect in a Family with Spondyloepiphyseal Dysplasia
AbstractSpondyloepiphyseal dysplasias (SED) are a heterogeneous group of inherited disorders characterized by disproportionate short stature and pleiotropic involvement of the skeletal and ocular systems. Evidence has suggested that SED may result from structural defects in type II collagen. To confirm the validity of this hypothesis, the structure of the "candidate" type II collagen gene (COL2A1) has been directly examined in a relatively large SED family. Coarse scanning of the gene by Southern blot hybridization identified an abnormal restriction pattern in one of the affected members of the kindred. Analysis of selected genomic fragments, amplified by the polymerase chain reaction, precisely localized the molecular defect and demonstrated that all affected family members carried the same heterozygous single-exon deletion. As a consequence of the mutation, nearly 90 percent of the assembled type II collagen homotrimers are expected to contain one or more procollagen subunits harboring an interstitial deletion of 36 amino acids in the triple helical domain.
American Journal of Medical Genetics Part A · 2010 · 60 citations · open access
Type IX collagen gene mutations can result in multiple epiphyseal dysplasia that is associated with osteochondritis dissecans and a mild myopathy
AbstractMultiple epiphyseal dysplasia (MED) is a clinically variable and genetically heterogeneous disease that is characterized by mild short stature and early onset osteoarthritis. Autosomal dominant forms are caused by mutations in the genes that encode type IX collagen, cartilage oligomeric matrix protein, and matrilin-3: COL9A1, COL9A2, COL9A3, COMP, and MATN3, respectively. Splicing mutations have been identified in all three genes encoding type IX collagen and are restricted to specific exons encoding an equivalent region of the COL3 domain in all three alpha(IX) chains. MED has been associated with mild myopathy in some families, in particular one family with a COL9A3 mutation and two families with C-terminal COMP mutations. In this study we have identified COL9A2 mutations in two families with MED that also have osteochondritis dissecans and mild myopathy. This study therefore extends the range of gene-mutations that can cause MED-related myopathy. (c) 2010 Wiley-Liss, Inc.
American Journal of Medical Genetics · 1998 · 31 citations
A large family with multiple epiphyseal dysplasia linked to COL9A2 gene
AbstractWe describe a large family, including 54 affected individuals, with multiple epiphyseal dysplasia (MED) with involvement of the peripheral joints only. In this family, a mutation in the COL9A2 gene was detected. Every affected person has involvement of the knee joints. Other involved joints are the elbow, ankle, wrist, hand, and feet joints. Involvement of the shoulder or hip joints is never seen after adolescence. The height of the affected individuals is short to normal; spinal involvement is never seen. The penetrance of the gene is complete. However, the expression of the gene is highly variable.
American Journal of Medical Genetics · 1993 · 16 citations
Exclusion of type II and type VI procollagen gene mutations in a five‐generation family with multiple epiphyseal dysplasia
AbstractWe have studied a family with an autosomal dominant form of multiple epiphyseal dysplasia (MED) inherited through at least 5 generations. Bilateral deformity of the hips with subsequent degenerative arthritis was the most common and most severe change observed in the affected relatives. Abnormalities of the knees, ankles, and shoulders were also noted in some affected individuals. Radiological examination showed changes in affected joints consistent with epiphyseal dysplasia. In early stages, the articular surfaces appeared flattened or irregular in shape. In advanced stages, epiphyseal fragmentation, joint surface erosion, and extensive remodeling were observed. The abnormalities of the epiphyses suggested that the primary defect might be in a structural component of the epiphyseal cartilage matrix. The gene encoding type II collagen (COL2A1) was tested for genetic linkage to MED in this family by restriction fragment length polymorphism (RFLP) analysis. Recombination between COL2A1 and MED was observed, ruling out COL2A1 as the site of the mutation. The genes encoding the 3 chains of type VI collagen were also excluded on the basis of discordant inheritance. The disease in this family is therefore not the result of mutations in the genes encoding type II or type VI collagen.
An Interesting Case of Multiple Epiphyseal Dysplasia Masquerading as Myopathy in a Southeast Asian Girl
AbstractMultiple epiphyseal dysplasia (MED) though one of the common skeletal dysplasias leads to a diagnostic dilemma. This is because the initial presentation is subtle in most of the cases which mimics other disorders like myopathies and rheumatological conditions. We present a case of a ten-year-old girl whose initial symptoms led to an extensive workup of myopathies yielding no conclusion. The final answer to the diagnosis was found through a genetic test. Most of the MED cases are because of mutation in the autosomal dominant gene which has variable penetrance leading to the absence of any family history. In this case too, family history was not significant.
American Journal of Medical Genetics Part C Seminars in Medical Genetics · 2012 · 1 citations
New topics in the skeletal dysplasias
AbstractA first glance at the table of contents of this issue might give the impression that we have chosen a disparate group of conditions to explore. However, we feel that this selection represents several key principles of the field and genetics, as well as medicine in general: these rare disorders need careful delineation and study so as not to be mistakenly lumped and inappropriately treated, molecular origins turn out to be more intricate and beautiful than previously imagined, and only through accurate recording can we move forward. Drs. Terhal and Mortier from the Netherlands and Belgium, together with clinical partners from several countries, have studied a large series of patients with mutations in the COL2A1 gene and elaborated new growth curves for spondylo-epiphyseal dysplasia congenital (SEDC) and related collagen 2 disorders. Development of these molecularly based growth curves is a major step forward in the nosography of collagen 2-related dysplasias, one of the largest and most important group of patients in a skeletal dysplasia clinic. Although variability remains significant and points to the multifactorial determination of height even in the presence of a single gene with a major influence, the possibility of comparing the growth chart of a single patient with that of a cohort of patients with similar mutations is a significant improvement over the past and projects us towards the future. It is hoped that similar studies will begin as soon as possible for all other major chondrodysplasia genes allowing the creation of a comprehensive database. In the best of worlds, such a database would include also data on morbidity and complications. The data presented by Drs. Terhal, Mortier and coworkers will undoubtedly constitute an important reference for years to come. The so-called enchondromatoses have been difficult to deal with in many a revision of the Nosology. Are they really “anarchic” development of bone or are they a special type of dysplasia? And what about their inheritance, so many cases being sporadic? Drs. Superti-Furga, Nishimura and Spranger have tried to tackle these questions with the help of recent results that have revealed unexpected molecular mechanisms. They suggest that enchondromas are useful but nonspecific findings and that the molecular bases include both homeostatic defects of bone resorption as well as true dysregulation of cell proliferation. In the latter group, the role of somatic mutations gives a novel twist to the story. The newly proposed classification and the presentation of reference images from molecularly proven individuals will prove to be a helpful companion for the clinician and radiologist. The Paris group led by Dr. Valerie Cormier-Daire contributes two articles illustrating the contribution of the study of genetic disorders to our understanding of skeletal biology and of human growth. In the article on “ciliary” disorders, Drs. Huber and Cormier take us into the world of monocilia, fascinating structures that stand like tall poles on the surface of most cells, including chondrocytes, receiving and transmitting signals—much like the antennas of cellular phones that today line the highways of modern countries—or, like in photoreceptors, carry large stacks of sensory molecules. The high morphologic and functional specialization of cilia is based on a complex transport and assembly apparatus (the intraflagellary transport system, IFT) and mutations in components of this apparatus affect proliferation and differentiation of cells. Based on the current state of knowledge in the skeletal dysplasias and in other ciliary disorders such as the Bardet–Biedl syndrome and the genetic nephropathies, Le Goff and Cormier predict that mutations in many more ciliary genes will be uncovered, and that genotype–phenotype correlations may involve di- or multigenic inheritance. In a further review, Drs. Le Goff and Cormier delineate the current knowledge on TGF signaling and growth disorders and report on the most recent discoveries on the “acromelic” dysplasias. How can single amino acid substitutions in fibrillin results in “opposite” disorders like Marfan syndrome and geleophysic dysplasia? The different effects on TGFβ signaling may be the explanation. The mutations discovered so far in different components of this system (TGFβ itself, its receptors at the cell membrane, the extracellular matrix protein system that binds TGFbeta and modulate its effects, and the intracellular TGFβ signal relay proteins such as the SMADs) reveal an unsuspected role of TGFβ signaling in growth and in the homeostasis of connective tissue. As ongoing studies on Marfan syndrome show, this is a potentially “druggable” system, and a full understanding may one day result in opportunities for novel treatments. Remember the surprise and enthusiasm when, in the mid-80s and 90s, the role of dominant mutations in the collagen 1 genes in producing osteogenesis imperfecta, the brittle bone disease, was identified? Concepts like “protein suicide” and dominant negative took their origin then, and the finding of gonadal and somatic mosaicism responsible for recurrences almost led to forget about the indications of the existence of recessive forms of OI. But the wind has turned, and no less than eight (and possibly more) genes responsible for recessive OI have been identified that not only disclose a complex machinery responsible for collagen assembly and secretion but also point to mechanisms of bone homeostasis that are independent of collagen. Drs. Giunta and Rohrbach from Zurich take us on a tour of these recent discoveries and lead us across the clinical and molecular classification of osteogenesis imperfecta. If the phenotype of fragile bones may have a myriad of different genetic causes, the calcium channel TRPV4 gives us an example of how a single molecule may result in a family of different phenotypes. The breakthrough finding of TRPV as the causative gene of dominant brachyolmia by Dr. Cohn and his colleagues in Los Angeles allowed a rapid series of subsequent articles adding several other disorders to the TRPV4 dysplasia family, including one of the prototypic conditions, metatropic dysplasia. Drs. Nishimura, Lausch, and Unger provide an accurate review of the skeletal phenotypes associated with TRPV4, a still somewhat mysterious molecule the dysfunction of which can produce skeletal or neurologic phenotypes and sometimes a combination of the two. Given that calcium channels are prominent candidates for pharmacologic blockade, some hope for a therapeutic approach in the future may be justified, but as outlined in the review, a more complete understanding of its functional context is needed. The article on the progressive pseudo-rheumatic dysplasia by Dr. Garcia-Segarra and Bonafé from the Lausanne center is a sobering reminder of the fact that the mere identification of a disease gene does not necessarily result in tangible advantage for affected individuals unless efforts are undertaken to explore the pathogenic mechanisms or, at least, to study its presenting signs and symptoms and to remind them to the practicing physicians. If a causative approach to the treatment of PPRD is still lacking over ten years later the discovery of its gene by the Warman group in 1999, the article by Drs. Garcia-Segarra and Bonafé and their coworkers reviews clinical manifestations, radiographic features and molecular findings in the largest PPRD patient series so far and will become an important reference for physicians seeking guidance in the diagnosis of this condition that is still recognized too late. Finally, Dr. Simon and coworkers from different continents present a clinical and pictorial essay on spondylo-megaepiphyseal-metaphyseal dysplasia emphasizing the neurologic complications. Indeed, the cervical spine complications in this dysplasia appear to be frequent and severe, resulting in deformities that are both spectacular on the imaging (kyknodysostosis of the cervical spine) and clinically devastating, as five of six patients reported had clinical spasticity. Awareness about this rare condition and early stabilization of the cervical spine may be important in ameliorating the prognosis in affected children. The AJMG editorial staff, and in particular Dr. John C. Carey, has been encouraging and helped us in any possible way. Our gratitude goes to them. At the end of May 2012, as we were busy in exchanging manuscripts with the Authors and editing them, we were struck by the announcement of the sudden disease of Dr. David L. Rimoin, a pioneer in the field of genetic diseases of bone, a giant of medical genetics, and a mentor and personal friend of many of us. The announcement of his death followed a few days later. The editing deadlines notwithstanding, we had to stop and grieve the loss. Although many in memoriam have already been written and more will follow, it would be impossible to release this volume to the skeletal dysplasia and medical genetics community without expressing our sorrow and grief for the loss of “DLR,” but also our recognition and gratitude for his generosity and the immense impulse and continuing support he has given to the field and to all those who worked with and around him. This special issue is dedicated to him and to his memory. DEDICATION To the memory of Dr. David L. Rimoin 1936–2012
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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