DeCure for Otopalatodigital syndrome spectrum disorder
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for otopalatodigital syndrome spectrum disorder — 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 moduleOtopalatodigital syndrome spectrum disorder 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 otopalatodigital syndrome spectrum disorder 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
filamin A (FLNA) — FLNA 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 diodrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2J3S · 2.5 Å · ligand 1,4-DIETHYLENE DIOXIDE (DIO). Experimental structure, not a prediction.
What the evidence adds up to
A novel FLNA point mutation (D203Y) in the actin-binding domain was identified in a sporadic female patient with otopalatodigital syndrome type 1 (OPD1). X-inactivation analysis showed an extremely skewed pattern towards the maternal chromosome. The patient presented with generalised skeletal dysplasia, mild mental retardation, hearing loss, cleft palate, and typical facial anomalies. OPD1 is one of the otopalatodigital syndrome spectrum disorders, which also include OPD2, Melnick-Needles syndrome, and frontometaphyseal dysplasia, all caused by mutations in the filamin A (FLNA) gene.
The crystal structure of filamin A immunoglobulin-like repeat 10 (FlnA-Ig10) was determined at 2.44 Å resolution. Mutations in this specific domain are correlated with Melnick-Needles syndrome and frontometaphyseal dysplasia, two severe forms of the spectrum. The structure provides insight into how these mutations may perturb the domain.
In two siblings with OPD2, a novel FLNA 629G>T mutation was found, predicting a C210F substitution in the second calponin homology domain of the actin-binding domain. This mutation arose de novo in the mother. One sibling was a macerated male stillborn with typical external and skeletal findings; a subsequent pregnancy was terminated after similar ultrasonographic findings. Histopathological studies showed osseous sclerosis and did not support a previously reported membranous ossification defect. The identical amino-acid substitution in the analogous position of beta-spectrin causes hereditary spherocytosis, but the same phenylalanine is normally present in utrophin and dystrophin without causing disease, indicating that the actin-binding domains of these proteins are not functionally equivalent.
No clinical trial data, no treatment intervention, and no drug repurposing evidence exist for any otopalatodigital syndrome spectrum disorder. What is missing is any therapeutic strategy, any preclinical model for drug screening, any patient stratification beyond genotype, and any funding for translational research aimed at modifying the course of these X-linked skeletal dysplasias.
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 · 2005 · 24 citations
A novel filamin A D203Y mutation in a female patient with otopalatodigital type 1 syndrome and extremely skewed X chromosome inactivation
AbstractOtopalatodigital syndrome type 1 (OPD1) [OMIM 311300] is an X-linked dominant multiple congenital anomalies disease mainly characterized by a generalized skeletal dysplasia, mild mental retardation, hearing loss, cleft palate, and typical facial anomalies. OPD1 belongs to a group of X-linked skeletal dysplasias known as oto-palato-digital syndrome spectrum disorders that also include OPD2, Melnick-Needles syndrome (MNS), and frontometaphyseal dysplasia (FMD). Recently, it has been demonstrated that mutations in the gene encoding the cytoskeletal protein Filamin A (FLNA) are responsible for this group of clinically overlapping human syndromes. We present the phenotypic and molecular data of a sporadic female patient clinically diagnosed with an OPD1 syndrome who carried a novel FLNA point mutation resulting in an Asp203Tyr substitution in the actin-binding domain of the protein. X-inactivation analyses demonstrated an extremely skewed pattern towards her maternal chromosome. Our results add to the molecular spectrum of the oto-palato-digital related syndromes and contribute to the delineation of phenotype-genotype correlation in this group of X-linked skeletal disorders.
Acta Crystallographica Section F Structural Biology and Crystallization Communications · 2011 · 16 citations · open access
Structure of filamin A immunoglobulin-like repeat 10 from<i>Homo sapiens</i>
AbstractFilamin A (FlnA) plays a critical role in cytoskeletal organization, cell motility and cellular signaling. FlnA utilizes different binding sites on a series of 24 immunoglobulin-like domains (Ig repeats) to interact with diverse cytosolic proteins and with cytoplasmic portions of membrane proteins. Mutations in a specific domain, Ig10 (FlnA-Ig10), are correlated with two severe forms of the otopalatodigital syndrome spectrum disorders Melnick-Needles syndrome and frontometaphyseal dysplasia. The crystal structure of FlnA-Ig10 determined at 2.44 Å resolution provides insight into the perturbations caused by these mutations.
American Journal of Medical Genetics Part A · 2007 · 11 citations
Otopalatodigital syndrome type 2 in two siblings with a novel filamin A 629G>T mutation: Clinical, pathological, and molecular findings
AbstractOtopalatodigital syndrome type 2 (OPD2) is an uncommon X-linked condition characterized by dysmorphic facies, a skeletal dysplasia affecting the axial and appendicular skeleton and extraskeletal anomalies including malformations of the brain, heart, genitourinary system, and intestines. Missense mutations of the FLNA gene, which encodes for the protein filamin A, have recently been shown to cause OPD2 and the allelic syndromes otopalatodigital type 1, Melnick-Needles, and frontometaphyseal dysplasia. Collectively these conditions constitute the otopalatodigital spectrum disorders. We report on two sibs affected by OPD2. The diagnosis was achieved at autopsy of a macerated male stillborn with typical external and skeletal findings of OPD2. A subsequent pregnancy was terminated due to ultrasonographic findings resembling those observed in the previous sibling. Histopathological studies revealed osseus sclerosis and do not support the previously reported membranous ossification defect observed in this condition. Mutation analysis demonstrated a novel mutation, 629G>T, in FLNA that had arisen de novo in the mother. This missense mutation predicts the substitution C210F within the second calponin homology domain of the actin-binding domain of filamin A. The identical substitution has been recently identified in an analogous amino-acid position within the actin binding domain of beta-spectrin leading to hereditary spherocytosis. The observation that phenylalanine is normally present in the same position in other proteins (utrophin, dystrophin) but leads to disease when present in filamin A implies that the function and/or structure of these actin binding domains are not entirely equivalent.
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.
