DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for MEDNIK syndrome — 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 moduleMEDNIK syndrome 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 mednik syndrome 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
adaptor related protein complex 1 subunit sigma 1 (AP1S1) — AP1S1 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 4P6Z · 3.0 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
MEDNIK syndrome is a rare autosomal recessive disease caused by variants in the AP1S1 gene, which encodes the σ1A subunit of the adaptor protein complex 1. A 2024 study reports two patients with the c.269 T > C missense variant (σ1A L90P) who presented with complete MEDNIK syndrome, contradicting earlier claims that this variant caused only non-syndromic congenital diarrhoea. Functional analyses show the L90P variant is largely unable to assemble into the AP-1 complex and fails to bind [DE]XXXL[LI] sorting motifs, resulting in loss of protein function. The authors conclude that all identified pathogenic AP1S1 variants result in MEDNIK syndrome.
A 2025 study describes two siblings with a homozygous AP1S1 splice-site mutation (c.430-1G>A). In vitro mRNA splicing experiments confirmed a single base-pair deletion in the fifth exon, causing a frameshift (p.Glu144ArgfsTer83). Both children showed developmental delays, seizures, yellow hair, sparse teeth, and a high forehead. The sister initially presented with intractable diarrhoea and severe pneumonia. Microscopic hair examination revealed deficient intermediate pigment, pale colour, and an intermittent or absent medulla. The authors note sparse teeth as a previously unreported feature.
Another 2025 report presents the first Italian case, a newborn with a new homozygous AP1S1 stop variant. The infant had congenital severe enteropathy and feeding-related seizures, described as an early and singular manifestation. Only 18 affected individuals with seven AP1S1 pathogenic variants have been reported in total, with high early lethality due to life-threatening enteropathy. Seven patients have been empirically treated with zinc acetate, but no controlled efficacy data are available. What remains missing is any systematic trial of zinc or other copper-modulating agents, a clear understanding of genotype-phenotype correlations given the small number of cases, and the funding needed to assemble an international cohort large enough to test interventions.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Molecular Medicine · 2024 · 4 citations · open access
Revising pathogenesis of AP1S1-related MEDNIK syndrome: a missense variant in the AP1S1 gene as a causal genetic lesion
AbstractMEDNIK syndrome is a rare autosomal recessive disease characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma, and caused by variants in the adaptor-related protein complex 1 subunit sigma 1 (AP1S1) gene. This gene encodes the σ1A protein, which is a subunit of the adaptor protein complex 1 (AP-1), a key component of the intracellular protein trafficking machinery. Previous work identified three AP1S1 nonsense, frameshift and splice-site variants in MEDNIK patients predicted to encode truncated σ1A proteins, with consequent AP-1 dysfunction. However, two AP1S1 missense variants (c.269 T > C and c.346G > A) were recently reported in patients who presented with severe enteropathy but no additional symptoms of MEDNIK. This condition was described as a novel non-syndromic form of congenital diarrhea caused specifically by the AP1S1 missense variants. In this study, we report two patients with the same c.269 T > C variant, who, contrary to the previous cases, presented as complete MEDNIK syndrome. These data substantially revise the presentation of disorders associated with AP1S1 gene variants and indicate that all the identified pathogenic AP1S1 variants result in MEDNIK syndrome. We also provide a series of functional analyses that elucidate the impact of the c.269 T > C variant on σ1A function, contributing to a better understanding of the molecular pathogenesis of MEDNIK syndrome. KEY MESSAGES: A missense AP1S1 c.269 T > C (σ1A L90P) variant causes full MEDNIK syndrome. The σ1A L90P variant is largely unable to assemble into the AP-1 complex. The σ1A L90P variant fails to bind [DE]XXXL[LI] sorting motifs. The σ1A L90P variant results in loss-of-function of the protein.
International Journal of Genomics · 2025 · 1 citations · open access
Clinical and Genetic Functional Validation of a Novel <i>AP1S1</i> Mutation Causing MEDNIK Syndrome
AbstractBackground: MEDNIK syndrome is a rare copper metabolism disorder caused by AP1S1 variants. Herein, we report the clinical and genetic characteristics of MEDNIK syndrome in two siblings. Methods: The clinical treatment process for MEDNIK syndrome and over 4 years of follow‐up data were analysed in two siblings. Microscopic observations of the patients’ hair were conducted. Gene sequencing, three‐dimensional structural reconstruction of protein sequences, and in vitro mRNA splicing experiments were performed. Results: The proband and his sister exhibited developmental delays, seizures, yellow hair, sparse teeth and a high forehead. Furthermore, the sister initially presented with intractable diarrhoea and severe pneumonia. Both siblings showed varying degrees of developmental delays during follow‐up, and the proband also showed symptoms of attention deficit hyperactivity disorder. The microscopic hair examination revealed a deficiency in intermediate pigment, a pale colour and an intermittent or absent medulla. Genetic sequencing revealed a homozygous AP1S1 mutation at the splicing site (NM_001283.3): c.430‐1G>A. The in vitro mRNA splicing experiments confirmed a single base‐pair deletion in the fifth exon of the mRNA sequence of the mutated plasmid, resulting in a frameshift mutation (p.Glu144ArgfsTer83). The mutation was inherited from both parents and classified as pathogenic according to the American College of Medical Genetics and Genomics guidelines, based on clinical features and family analysis. Conclusion: Both children with MEDNIK syndrome exhibited heterogeneous clinical phenotypes. Sparse teeth may be a previously unnoticed feature of MEDNIK syndrome. The pathogenic c.430‐1G>A homozygous variant enriches the mutation spectrum of AP1S1 . This mutation causes a frameshift mutation in the protein, altering the protein structure and affecting protein function.
Journal of Clinical Medicine · 2025 · 0 citations · open access
Feeding-Triggered Seizures in a Newborn with AP1S1-Related MEDNIK Syndrome: Expanding the Phenotype of a Hyper-Rare Disease
AbstractMEDNIK syndrome (Mental Retardation, Enteropathy, Deafness, Neuropathy, Ichthyosis and Keratodermia) is a severe hyper-rare condition resulting from the biallelic variants in the AP1S1 gene, implicated in intracellular trafficking and copper homeostasis. Only 18 affected individuals (seven AP1S1 pathogenic variants overall) have been reported to date, with a high early lethality due to life-threatening congenital enteropathy. Seven patients have been empirically treated with zinc. Due to the paucity of literature data, little is known about the clinical course of individuals affected by MEDNIK syndrome, and the possible early association with epilepsy needs to be investigated. We present the first case of Italian origin affected by MEDNIK syndrome carrying a new homozygous AP1S1 stop variant, presenting with congenital severe enteropathy and feeding-related seizures, thus representing an early, singular manifestation of the disease. We describe her clinical course and the zinc acetate therapeutic experience. We also reviewed the literature focusing on clinical manifestations (especially neurological), brain neuroimaging and the symptom evolution of patients with AP1S1-related MEDNIK syndrome and discuss possible future therapeutic attempts.
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.
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