DeCure for Intellectual disability, autosomal recessive 56
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for intellectual disability, autosomal recessive 56 — 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 56 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 56 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 missense mutation in MED23 (p.R617Q) was found to segregate with nonsyndromic autosomal recessive intellectual disability in one family. The mutation impaired the response of JUN and FOS immediate early genes to serum mitogens by disrupting the interaction between enhancer-bound transcription factors and Mediator. Transcriptional dysregulation of these genes was also seen in cells from patients with other neurological disorders linked to mutations in other Mediator subunits. The authors suggested that altered immediate early gene expression might be a common molecular feature of cognitive deficit.
Three unrelated consanguineous families with biallelic pathogenic variants in NSUN6 were identified. Two variants were predicted loss-of-function; one led to absence of NSUN6 via nonsense-mediated decay, the other encoded a protein that did not fold correctly. A missense variant in the third family lost enzymatic activity and could not bind the methyl donor S-adenosyl-L-methionine. Affected individuals had developmental delay, intellectual disability, motor delay, and behavioural anomalies. Homozygous ablation of the NSUN6 ortholog in Drosophila caused locomotion and learning impairment. The authors concluded that biallelic NSUN6 variants cause a form of autosomal recessive intellectual disability.
A 2022 review noted that autosomal recessive intellectual disability accounts for most molecular diagnoses in inbred populations, but most published cohort studies have revealed the important contribution of de novo variants. A separate case report described a patient with a de novo heterozygous nonsense variant in TRIP12 (c.40C>T, p.Arg14X), classified as pathogenic, causing autosomal dominant intellectual disability. A 2022 review of mouse models of Bardet-Biedl Syndrome stated that there are limited pharmacological interventions for intellectual disability, partially due to poor understanding of its heterogeneous nature and a lack of mouse models. A 2022 review on homoeopathic management of intellectual disability claimed homoeopathy would remove the disease from the root cause but provided no data.
What is still missing: large-scale functional studies linking specific Mediator or RNA-modification variants to patient outcomes, any clinical trial of a drug targeting these pathways, and patient stratification by genetic subtype. The homoeopathic claim lacks any evidence from controlled studies.
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.
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.
Journal of Medical Genetics · 1987 · 14 citations · open access
Spondyloepiphyseal dysplasia tarda: a new autosomal recessive variant with mental retardation.
AbstractA new variant of spondyloepiphyseal dysplasia tarda with mild to moderate mental retardation is described in three daughters born to healthy, consanguineous parents. The mode of inheritance is compatible with that of an autosomal recessive disorder. The identification of this variant is important, as it enables more precise counselling in families in which sporadic cases with this form of presentation are found.
International Journal of Homoeopathic Sciences · 2022 · 0 citations · open access
An overall review on intellectual disability disorder and its homoeopathic management
AbstractThe Intellectual Disability Disorder is found as a one of the clinical manifestations of the rare disorders which occupies a total prevalence of about 6 to 8% globally. The rare disorder is found to cause many of the chronic disabilities in which the intellectual disability disorder is one of them which has a drastic impact on the individual who is affected and their families and includes the health care system. The onset period of the rare disorder begins from the prenatal period into the late adulthood and it is being assessed that about the half of the individual affected are children [1]. The prime and the only purpose of this study undertaken is to find the effectiveness of the homoeopathic medicine in the treatment of the Intellectual Disability Disorder and also to alter their intellectual and the adaptive functions of the affected individual. The homoeopathic medicine will remove the disease from the root cause.
[Intellectual disability due to heterozygous c.40C>T variant of TRIP12 gene in a patient].
AbstractOBJECTIVE: To explore the genetic basis for a patient with intellectual disability. METHODS: Whole exome sequencing and Sanger sequencing were carried out for the patient. The result was verified in her family. RESULTS: DNA sequencing revealed that the patient has carried a heterozygous nonsense c.40C>T (p.Arg14X) variant of the TRIP12 gene, which was de novo in origin. The variant was unrecorded in the Human Gene Mutation Database. Based on the American College of Medical Genetics and Genomics standards and guidelines, the variant was predicted to be pathogenic (PVS1+ PS2+ PP3). CONCLUSION: The patient was diagnosed with autosomal dominant intellectual disability due to heterozygous c.40C>T variant of the TRIP12 gene.
Iowa Research Online (The University of Iowa) · 2022 · 0 citations · open access
Behavioral and brain phenotypes of mouse models of Bardet-Biedl Syndrome
AbstractIntellectual disability (ID) is one of the most common neurodevelopmental disorders, affecting 1% of the population globally. Clinically, ID is characterized by a deficit in intellectual functioning and adaptive functioning. There are limited pharmacological interventions for ID, partially due to a poor understanding of ID and the heterogeneous nature of ID In addition, there are limited mouse models of ID.
Majmaah Journal of Health Sciences · 2021 · 0 citations · open access
Review On Clinical And Molecular Genetics Of Autosomal Recessive Intellectual Disability
AbstractIntellectual disability (ID) is a relatively common phenotype with multiple etiologies. Recent progress in the genetics of ID greatly expanded our understanding of the biological defects underlying this clinical entity. While most published cohort genetic studies on ID revealed the important contribution of de novo (germline or postzygotic) variants, we focused in this study of autosomal recessive ID (ARID), that account for most of the molecular bases in ID cases in inbred populations. We discussed the current state of ARID from a clinical, molecular and genetics standpoints.
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.
