DeCure for Intellectual developmental disorder, X-linked 108
DeCure's autonomous Psychiatry AI scientist is researching a drug-repurposing hypothesis for intellectual developmental disorder, X-linked 108 — 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 moduleIntellectual developmental disorder, X-linked 108 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 intellectual developmental disorder, x-linked 108 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
IQ motif and Sec7 domain ArfGEF 2 (IQSEC2) — IQSEC2 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 6FAE · 2.35 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
The 2016 study of the MRX78 family, which includes six affected males and seven affected females, identified a missense mutation (c.C2366T, p.A789V) in the IQSEC2 gene as the cause of X-linked intellectual disability in that family. Functional assays showed that the recombinant IQSEC2(A789V) protein could not catalyse GDP-GTP exchange on Arf6 as efficiently as the wild-type protein. The mutation was predicted to disrupt the folding of the catalytic Sec7 domain.
Two abstracts from 2011 and 2018 discuss fragile X syndrome (FXS), the most common inherited form of intellectual disability, which is caused by a different gene (FMR1). The 2011 review states that current medical practices aim to relieve symptoms, not alter underlying cognitive deficits, but suggests that pharmaceutical therapies targeting FXS may become a benchmark for CNS drug discovery. The 2018 industry perspective notes that over 25 years of research have identified several potential targeted therapeutics, some tested in clinical trials, and that the pharmaceutical industry is becoming more involved. Neither abstract reports any drug that has demonstrated efficacy in altering cognitive deficits in FXS.
A 2015 study reports a novel NLGN4X splicing mutation (g.1202C>A) in two brothers with non-syndromic X-linked intellectual disability. The mother was heterozygous with a skewed X inactivation pattern (100%) and was not affected. The mutation was absent in an unaffected daughter. The study does not report any treatment or intervention.
No drug has been shown to treat intellectual developmental disorder, X-linked 108, or any of the genetic forms of intellectual disability described in these abstracts. What is missing are completed clinical trials that demonstrate a drug can alter cognitive deficits, patient stratification by specific genetic mutation, and funding for such trials.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Brain Sciences · 2018 · 33 citations · open access
Clinical Development of Targeted Fragile X Syndrome Treatments: An Industry Perspective
Abstract) gene, resulting in a deficit of fragile X mental retardation protein (FMRP). The clinical presentation of FXS is variable, and is typically associated with developmental delays, intellectual disability, a wide range of behavioral issues, and certain identifying physical features. Over the past 25 years, researchers have worked to understand the complex relationship between FMRP deficiency and the symptoms of FXS and, in the process, have identified several potential targeted therapeutics, some of which have been tested in clinical trials. Whereas most of the basic research to date has been led by experts at academic institutions, the pharmaceutical industry is becoming increasingly involved with not only the scientific community, but also with patient advocacy organizations, as more promising pharmacological agents are moving into the clinical stages of development. The objective of this review is to provide an industry perspective on the ongoing development of mechanism-based treatments for FXS, including identification of challenges and recommendations for future clinical trials.
Frontiers in Molecular Neuroscience · 2016 · 27 citations · open access
Novel Missense Mutation A789V in IQSEC2 Underlies X-Linked Intellectual Disability in the MRX78 Family
AbstractDisease gene discovery in neurodevelopmental disorders, including X-linked intellectual disability (XLID) has recently been accelerated by next-generation DNA sequencing approaches. To date, more than 100 human X chromosome genes involved in neuronal signaling pathways and networks implicated in cognitive function have been identified. Despite these advances, the mutations underlying disease in a large number of XLID families remained unresolved. We report the resolution of MRX78, a large family with six affected males and seven affected females, showing X-linked inheritance. Although a previous linkage study had mapped the locus to the short arm of chromosome X (Xp11.4-p11.23), this region contained too many candidate genes to be analyzed using conventional approaches. However, our X-chromosome exome resequencing, bioinformatics analysis and inheritance testing revealed a missense mutation (c.C2366T, p.A789V) in IQSEC2, encoding a neuronal GDP-GTP exchange factor for Arf family GTPases (ArfGEF) previously implicated in XLID. Molecular modeling of IQSEC2 revealed that the A789V substitution results in the insertion of a larger side-chain into a hydrophobic pocket in the catalytic Sec7 domain of IQSEC2. The A789V change is predicted to result in numerous clashes with adjacent amino acids and disruption of local folding of the Sec7 domain. Consistent with this finding, functional assays revealed that recombinant IQSEC2(A789V) was not able to catalyze GDP-GTP exchange on Arf6 as efficiently as wild-type IQSEC2. Taken together, these results strongly suggest that the A789V mutation in IQSEC2 is the underlying cause of XLID in the MRX78 family.
ACS Chemical Neuroscience · 2011 · 19 citations · open access
Fragile X Syndrome: An Update on Developing Treatment Modalities
AbstractIntellectual disability (ID; mental retardation) is considered an immutable condition. Current medical practices are aimed at relieving symptoms and not at altering the underlying cognitive deficits. Scientific advancements from the past decade have led to the exciting possibility that ID may now be treatable. Moreover, pharmaceutical therapies targeting the most common form of inherited ID, Fragile X syndrome (FXS), may become the new benchmark for central nervous system (CNS) drug discovery: seeking cures for neurodevelopmental disorders.
Medicine Science | International Medical Journal · 2018 · 2 citations · open access
Psychiatric aspects of 47, XYY (Jacobs) syndrome: A case report
AbstractIn this case, psychiatric aspects of 47, XYY syndrome is discussed in a male adolescent patient diagnosed with Attention Deficit Hyperactivity Disorder (ADHD), conduct disorder (CD), mild intellectual disability, and Tourette syndrome. A 13-year-old boy was diagnosed with ADHD, CD, mild intellectual disability, Tourette syndrome, and 47, XYY syndrome. As in our case, the presence of the XYY syndrome with Tourette syndrome, ADHD, CD and mild intellectual disability is the first demonstrative case. As it is known that XYY syndrome can often lead to neurodevelopmental disorders, genetic counseling can be provided when more than one neurodevelopmental disorders are detected as comorbid. [Med-Science 2018; 7(2.000): 446-7]
Greater South Information System · 2015 · 0 citations · open access
Non-Syndromic X Linked Intellectual Disability in Two Brothers with A Novel NLGN4X Gene Splicing Mutation (NC_018934.2: g. 1202C>A)
AbstractX-linked Intellectual Disability (XLID) is an extremely heterogeneous disorder for which many of the causative genes are still unknown.So far, more than one hundred genes of the X chromosome have been found to be altered in males manifesting intellectual disability (ID).NLGN4X is an XLID gene, which has been found, involved in autism and Asperger syndrome involving causative coding mutations.Up to now a few pathological mutations in the promoter and the 5' UTR have been identified.Here we report a non-syndromic X linked Intellectual disability in two brothers with a novel NLGN4X splicing mutation predicted to have a pathogenic effect by the activation of an exonic cryptic acceptor site, with presence of one or more cryptic branch point(s).This mutation g.1202C>A (Genbank accession number NC_018934.2) was identified through X exome sequencing.It was confirmed by Sanger sequencing.The mother was heterozygous with a skewed X inactivation pattern (100%).She is not affected.This variant was predicted to change the splicing process leading to potential alteration of the mRNA.This mutation segregates with the pathological phenotype in all the affected males.However, it was absent in the non-affected daughter, we suggest that it could be in favor of genotype-phenotype correlation.This study also confirms the efficiency of X exome sequencing for identifying specific genetic conditions not clinically suspected.
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.
