DeCure for Maturity-onset diabetes of the young type 4
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for maturity-onset diabetes of the young type 4 — 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 moduleMaturity-onset diabetes of the young type 4 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 maturity-onset diabetes of the young type 4 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
glucokinase (GCK) — GCK 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 2rdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4DCH · 1.79 Å · ligand (2R)-3-cyclopentyl-2-[4-(methylsulfonyl)phenyl]-N-(1,3-thiazol-2-yl)propanamide (4DC). Experimental structure, not a prediction.
What the evidence adds up to
A Swiss family with 13 diabetic patients over three generations carried a novel V121I mutation in HNF4A, the gene responsible for MODY1. The average age at diagnosis in that family was 35 plus or minus 15 years, with seven subjects diagnosed before age 30, and two additional individuals had an abnormal oral glucose tolerance test. The mutation segregated in all MODY patients and was located in the DNA binding domain, a strongly conserved region. Identification of the mutation allowed presymptomatic diagnosis in younger generations. Loss-of-function HNF4A mutations cause progressive loss of beta-cell function and eventually frank hyperglycaemia denominated as MODY1, and have also been associated with type 2 diabetes and gestational diabetes.
Three novel PAX4 variants were identified in three unrelated patients with early-onset diabetes and a family history of the disease, in a study of MODY9, a rare subtype caused by PAX4 variants. The variants were c.83delA (p.Gln28ArgfsTer6), c.35T>C (p.Leu12Pro), and c.488G>C (p.Arg163Pro). Expression of the frameshift variant was undetectable, likely due to nonsense-mediated decay. The two missense mutants retained nuclear localisation but showed markedly reduced protein levels. Treatment with the proteasome inhibitor MG132 restored protein levels of the missense mutants, indicating enhanced proteasomal degradation as the mechanism. The study concluded that certain PAX4 variants impair beta-cell function by destabilising the protein post-translationally.
No abstract reports a treatment trial, a drug intervention, or any clinical outcome beyond genetic diagnosis and characterisation. The 2002 paper describes only family segregation and presymptomatic diagnosis. The 2014 paper is a general description of HNF4A-associated MODY1. The 2025 paper is a laboratory study of protein degradation pathways in mouse cells. There is no evidence for any drug that modifies the course of MODY4 or any other MODY subtype in these abstracts.
What is missing is any clinical trial testing a drug in patients with confirmed MODY4, any patient-level outcome data such as glycaemic control or complication rates after an intervention, and any stratification by specific mutation type. The functional work on PAX4 variants suggests a possible target for proteasome inhibition, but that has not been tested in humans, and no funding or trial design for such a study is described.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Human Mutation · 2002 · 11 citations · open access
Large Family With Maturity-Onset Diabetes of the Young and a Novel V121I Mutation in HNF4A
AbstractMaturity-onset diabetes of the young (MODY) is a subtype of early-onset diabetes mellitus which is characterized by autosomal dominant inheritance. Several genes are known to induce MODY : HNF4A/MODY1, GCK/MODY2, TCF1/MODY3, IPF1/MODY4, TCF2/MODY5 and NEUROD1/MODY6. We studied a Swiss family with 13 diabetic patients over 3 generations. The average age at diagnosis was 35 +/- 15 years (7 subjects before 30). In addition, 2 individuals had an abnormal oral glucose tolerance. The mutation present in this family was located in the DNA binding domain of HNF4A, a strongly conserved region across almost all species, and segregated in all the MODY patients. Identification of this missense mutation allowed for presymptomatic diagnosis in the younger generations and will improve medical follow-up of the predisposed individuals.
The Italian Journal of Pediatrics/Italian journal of pediatrics · 2014 · 3 citations · open access
Clinical heterogeneity of abnormal glucose homeostasis associated with the HNF4A R311H mutation
AbstractMaturity Onset Diabetes of the Young (MODY; MIM# 606391) represents a genetically and clinically heterogeneous form of diabetes mellitus (DM) [1-3], characterized by hyperglycaemia or overt diabetes, in at least two or three consecutive generations, onset <25 years of age, absence of anti -cells antibodies. Loss-of-function HNF4A mutations cause a progressive loss of -cell function [4] and, eventually, frank hyperglycaemia denominated as MODY1. HNF4A mutations have been associated with MODY1, type 2 diabetes and gestational diabetes (GDM)
Journal of the Association of Physicians of India · 2025 · 1 citations
Exciting Discovery of a New Maturity-onset Diabetes of the Young Subtype from India (MODY 15)
AbstractAt that time, the classification of diabetes was based purely on the age at onset of diabetes. Those diagnosed with diabetes below 40 years of age were labeled as "growth onset diabetes," while those with onset at or above the age of 40 years were referred to as "maturity onset diabetes." At that time, these types were believed to be equivalent to what are known as type 1 diabetes (T1D) and type 2 diabetes (T2D) today.
BMJ Open Diabetes Research & Care · 2025 · 0 citations · open access
Identification and characterization of novel <i>PAX4</i> variants in patients with suspected MODY9
AbstractIntroduction Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes. MODY type 9 (MODY9) is a rare subtype caused by variants in the PAX4 gene. However, the pathogenicity and mechanisms of many PAX4 variants remain unclear. This study aimed to evaluate the clinical relevance and pathogenic mechanisms of three novel PAX4 variants identified in patients with suspected MODY. Research design and methods Three unrelated patients with early-onset diabetes and a family history of the disease were screened for PAX4 variants using whole-exome and Sanger sequencing. In silico predictions, evolutionary conservation analysis, and structural modeling were performed. Functional studies were conducted in MIN6 cells to assess protein expression, subcellular localization, and degradation pathways. Results Three novel PAX4 variants (c.83delA; p.Gln28ArgfsTer6, c.35T>C; p.Leu12Pro, and c.488G>C; p.Arg163Pro) were identified. Expression of p.Gln28ArgfsTer6 was undetectable, likely due to nonsense-mediated decay. In contrast, p.Leu12Pro and p.Arg163Pro retained nuclear localization but resulted in markedly reduced protein levels. Treatment with the proteasome inhibitor MG132 restored protein levels of the missense mutants, indicating enhanced proteasomal degradation as the likely mechanism. These findings suggest that certain PAX4 variants impair β-cell function by destabilizing the protein post-translationally. Conclusions This study expands the spectrum of PAX4 variants and provides novel mechanistic insights into the pathogenesis of MODY9. Our results highlight the importance of assessing protein-level consequences for variant interpretation and support the integration of functional assays into MODY genetic diagnostic workflows.
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.
