DeCure for Intellectual disability, autosomal recessive 1
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for intellectual disability, autosomal recessive 1 — 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 moduleIntellectual disability, autosomal recessive 1 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 intellectual disability, autosomal recessive 1 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.
What the evidence adds up to
A 2011 study of a single consanguineous family identified a missense mutation (p.R617Q) in MED23 that cosegregated with nonsyndromic autosomal recessive intellectual disability. In cell assays, this mutation specifically impaired the response of JUN and FOS immediate early genes to serum mitogens by disrupting the interaction between enhancer-bound transcription factors (TCF4 and ELK1) and the Mediator complex. The same transcriptional dysregulation was observed in cells from patients with other neurological disorders linked to mutations in different Mediator subunits or interacting proteins. The authors proposed that altered immediate early gene expression might be a common molecular feature of cognitive deficit.
A 2023 study reported three unrelated consanguineous families with deleterious homozygous variants in NSUN6, a gene encoding an RNA methyltransferase. Two variants were predicted loss-of-function: one in the first exon expected to trigger nonsense-mediated decay, and one in the last exon that produced a misfolded protein. The third family carried a missense variant that lost enzymatic activity and could not bind the methyl donor S-adenosyl-L-methionine. Affected individuals presented with developmental delay, intellectual disability, motor delay, and behavioural anomalies. Homozygous knockout of the NSUN6 ortholog in Drosophila caused locomotion and learning impairment. The authors concluded that biallelic pathogenic variants in NSUN6 cause one form of autosomal recessive intellectual disability, establishing another link between RNA modification and cognition.
A 2021 case series on antenatal counselling for developmental delay and intellectual disability noted that the aetiology of these conditions is diverse, that subtle clinical markers may point to an underlying genetic cause, and that genetic counselling has a robust role. The authors cautioned that investigations should be advised judiciously to balance anticipated gains with expenses, especially in resource-limited settings.
No drug treatment is mentioned in any of these abstracts. What is still missing is any therapeutic strategy: no compound has been tested against MED23 or NSUN6 mutations, no preclinical model has been used for drug screening, and no trial design exists. Patient stratification remains rudimentary, relying on single-family or small consanguineous cohorts. Funding for functional assays and for any attempt at repurposing or developing a molecule is absent.
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 · 2011 · 118 citations
<i>MED23</i> Mutation Links Intellectual Disability to Dysregulation of Immediate Early Gene Expression
AbstractMED23 is a subunit of the Mediator complex, a key regulator of protein-coding gene expression. Here, we report a missense mutation (p. R617Q) in MED23 that cosegregates with nonsyndromic autosomal recessive intellectual disability. This mutation specifically impaired the response of JUN and FOS immediate early genes (IEGs) to serum mitogens by altering the interaction between enhancer-bound transcription factors (TCF4 and ELK1, respectively) and Mediator. Transcriptional dysregulation of these genes was also observed in cells derived from patients presenting with other neurological disorders linked to mutations in other Mediator subunits or proteins interacting with MED. These findings highlight the crucial role of Mediator in brain development and functioning and suggest that altered IEG expression might be a common molecular hallmark of cognitive deficit.
Genetics in Medicine · 2023 · 20 citations · open access
Biallelic variants in NSUN6 cause an autosomal recessive neurodevelopmental disorder
AbstractPURPOSE: 5-methylcytosine RNA modifications are driven by NSUN methyltransferases. Although variants in NSUN2 and NSUN3 were associated with neurodevelopmental diseases, the physiological role of NSUN6 modifications on transfer RNAs and messenger RNAs remained elusive. METHODS: We combined exome sequencing of consanguineous families with functional characterization to identify a new neurodevelopmental disorder gene. RESULTS: We identified 3 unrelated consanguineous families with deleterious homozygous variants in NSUN6. Two of these variants are predicted to be loss-of-function. One maps to the first exon and is predicted to lead to the absence of NSUN6 via nonsense-mediated decay, whereas we showed that the other maps to the last exon and encodes a protein that does not fold correctly. Likewise, we demonstrated that the missense variant identified in the third family has lost its enzymatic activity and is unable to bind the methyl donor S-adenosyl-L-methionine. The affected individuals present with developmental delay, intellectual disability, motor delay, and behavioral anomalies. Homozygous ablation of the NSUN6 ortholog in Drosophila led to locomotion and learning impairment. CONCLUSION: Our data provide evidence that biallelic pathogenic variants in NSUN6 cause one form of autosomal recessive intellectual disability, establishing another link between RNA modification and cognition.
Journal of Pediatric Neurology and Neuroscience · 2021 · 0 citations · open access
Antenatal Counselling in Developmental Delay and Intellectual Disability: Case Series
AbstractIntellectual disability and developmental delay are is common presentations encountered in pediatric clinical practice. Etiology of these illnesses is diverse. Subtle clinical markers may act as pointers to underlying genetic etiology in some of these conditions. Due to the increased availability of genetic tests. There is a robust role of genetic counseling in many of these conditions. However, investigations need to be judiciously advised to balance the anticipated gains with the expenses, more so in resource-limited settings.
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.
