DeCure for Syndromic X-linked intellectual disability Claes-Jensen type
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for syndromic X-linked intellectual disability Claes-Jensen type — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleSyndromic X-linked intellectual disability Claes-Jensen type maps to a 2-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 syndromic x-linked intellectual disability claes-jensen type 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
lysine demethylase 5C (KDM5C) — KDM5C 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 2-{[(edrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5FWJ · 2.1 Å · ligand 2-{[(2-{[(E)-2-(dimethylamino)ethenyl](ethyl)amino}-2-oxoethyl)amino]methyl}pyridine-4-carboxylic acid (MMK). Experimental structure, not a prediction.
What the evidence adds up to
A missense mutation in CLIC2, p.H101Q, was identified in a male with X-linked intellectual disability and was not found in healthy individuals. In silico modelling predicted that this mutation reduces flexibility of a joint loop important for normal CLIC2 function, stabilises the overall 3D structure in a way that may prevent a necessary conformational change, and removes a positively charged residue possibly needed for membrane association. The same paper notes that numerous non-synonymous SNPs in CLIC2 are found in healthy people, meaning the protein can tolerate amino acid substitutions and remain fully functional; the authors suggest p.H101Q may be the first disease-causing mutation proposed in the CLIC family, based on modelling and polymorphism analysis alone.
A separate family study identified a deletion in Xp22.11 containing only the PTCHD1 gene in two boys with severe neurodevelopmental disorder and X-linked inheritance. The exact function of PTCHD1 is unknown, but its encoded protein contains a patched domain involved in the sonic hedgehog pathway, and the gene is expressed in human cortex and cerebellum. The authors propose PTCHD1 as a candidate gene for X-linked intellectual disability with or without autism, based on this single family.
The most frequently mutated XLID genes after FMR1 and MECP2 include ARX, with over 110 reported mutations. The phenotype always involves intellectual disability and often epilepsy, infantile spasms, hand dystonia, lissencephaly, autism, or dysarthria. KDM5C, a histone demethylase that regulates transcription by altering chromatin, is genetically linked to Claes-Jensen syndrome. Research in model organisms has shown KDM5C is important for neuronal development and function, but how it controls transcriptional programs within neurons to impact growth and activity remains under investigation. A 2013 review notes that 102 XLID genes have been identified and that the proteins they encode are involved in higher brain functions such as cognition, learning, and memory.
No drug is mentioned in any of these abstracts. No clinical trial, no treatment, no intervention is tested or proposed. What is missing is any therapy development pipeline: no drug screening, no repurposing candidates, no animal model testing of compounds, no patient stratification beyond genetic diagnosis, and no funding directed toward pharmacological intervention for Claes-Jensen syndrome specifically.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Proteins Structure Function and Bioinformatics · 2011 · 104 citations
A missense mutation in <i>CLIC2</i> associated with intellectual disability is predicted by <i>in silico</i> modeling to affect protein stability and dynamics
AbstractLarge-scale next generation resequencing of X chromosome genes identified a missense mutation in the CLIC2 gene on Xq28 in a male with X-linked intellectual disability (XLID) and not found in healthy individuals. At the same time, numerous nsSNPs (nonsynonomous SNP) have been reported in the CLIC2 gene in healthy individuals indicating that the CLIC2 protein can tolerate amino acid substitutions and be fully functional. To test the possibility that p.H101Q is a disease-causing mutation, we performed in silico simulations to calculate the effects of the p.H101Q mutation on CLIC2 stability, dynamics, and ionization states while comparing the effects obtained for presumably harmless nsSNPs. It was found that p.H101Q, in contrast with other nsSNPs, (a) lessens the flexibility of the joint loop which is important for the normal function of CLIC2, (b) makes the overall 3D structure of CLIC2 more stable and thus reduces the possibility of the large conformational change expected to occur when CLIC2 moves from a soluble to membrane form, and (c) removes the positively charged residue, H101, which may be important for the membrane association of CLIC2. The results of in silico modeling, in conjunction with the polymorphism analysis, suggest that p.H101Q may be a disease-causing mutation, the first one suggested in the CLIC family.
Deletion in Xp22.11: PTCHD1 is a candidate gene for X-linked intellectual disability with or without autism
AbstractFilges I, Röthlisberger B, Blattner A, Boesch N, Demougin P, Wenzel F, Huber AR, Heinimann K, Weber P, Miny P. Deletion in Xp22.11: PTCHD1 is a candidate gene for X-linked intellectual disability with or without autism. Submicroscopic chromosomal anomalies play an important role in the aetiology of intellectual disability (ID) and have been shown to account for up to 10% of non-syndromic forms. We present a family with two affected boys compatible with X-linked inheritance of a phenotype of severe neurodevelopmental disorder cosegregating with a deletion in Xp22.11 exclusively containing the PTCHD1 gene. Although the exact function of this gene is unknown to date, the structural overlap of its encoded patched domain-containing protein 1, the transmembrane protein involved in the sonic hedgehog pathway, and its expression in human cortex and cerebellum as well as in mice and drosophila brain suggests a causative role of its nullisomy in the developmental phenotype of our family. Our findings support the recent notions that PTCHD1 may play a role in X-linked intellectual disability (XLID) and autism disorders.
The Neurobiology of X-Linked Intellectual Disability
AbstractX-linked intellectual disability (XLID) affects 1% to 3% of the population. XLID subsumes several heterogeneous conditions, all of which are marked by cognitive impairment and reduced adaptive skills. XLID arises from mutations on the X chromosome; to date, 102 XLID genes have been identified. The proteins encoded by XLID genes are involved in higher brain functions, such as cognition, learning and memory, and their molecular role is the subject of intense investigation. Here, we review recent findings concerning a representative group of XLID proteins: the fragile X mental retardation protein; methyl-CpG-binding protein 2 and cyclin-dependent kinase-like 5 proteins, which are involved in Rett syndrome; the intracellular signaling molecules of the Rho guanosine triphosphatases family; and the class of cell adhesion molecules. We discuss how XLID gene mutations affect the structure and function of synapses.
Molecular and cellular events linking variants in the histone demethylase KDM5C to the intellectual disability disorder Claes‐Jensen syndrome
AbstractThe widespread availability of genetic testing for those with neurodevelopmental disorders has highlighted the importance of many genes necessary for the proper development and function of the nervous system. One gene found to be genetically altered in the X-linked intellectual disability disorder Claes-Jensen syndrome is KDM5C, which encodes a histone demethylase that regulates transcription by altering chromatin. While the genetic link between KDM5C and cognitive (dys)function is clear, how KDM5C functions to control transcriptional programs within neurons to impact their growth and activity remains the subject of ongoing research. Here, we review our current knowledge of Claes-Jensen syndrome and discuss important new data using model organisms that have revealed the importance of KDM5C in regulating aspects of neuronal development and function. Continued research into the molecular and cellular activities regulated by KDM5C is expected to provide critical etiological insights into Claes-Jensen syndrome and highlight potential targets for developing therapies to improve the quality of life of those affected.
Oxford University Press eBooks · 2016 · 3 citations
Developmental Abnormalities Due to Mutations in the Aristaless-Related Homeobox Gene
AbstractAbstract Intellectual disability is a broad spectrum of neurodevelopmental disorders of the brain that combined affect approximately one in 50 individuals worldwide. X-linked intellectual disabilities represent a group of disorders where mutations arise on the X-chromosome. XLID is clinically complex and genetically heterogeneous. In excess of 100 genes are currently known. One of the most frequently mutated XLID genes (after e.g. FMR1 or MECP2) is the Aristaless related homeobox (ARX) gene. More than 110 mutations have been reported in ARX. The phenotype always involves intellectual disability and often also epilepsy, infantile spasms, hand dystonia, lissencephaly, autism or dysarthria. This chapter summarizes currently known mutations in ARX and their clinical manifestations and explores what is known about the underlying molecular and cellular mechanisms.
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.
