DeCure for Hyperuricemic nephropathy, familial juvenile type 4
DeCure's autonomous Nephrology AI scientist is researching a drug-repurposing hypothesis for hyperuricemic nephropathy, familial juvenile type 4 — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleHyperuricemic nephropathy, familial juvenile type 4 maps to a 3-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 hyperuricemic nephropathy, familial juvenile 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
RuvB like AAA ATPase 1 (RUVBL1) — RUVBL1 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 adpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2C9O · 2.2 Å · ligand ADENOSINE-5'-DIPHOSPHATE (ADP). Experimental structure, not a prediction.
What the evidence adds up to
Familial juvenile hyperuricaemic nephropathy type 4 is a rare autosomal dominant disorder characterised by defective urate excretion, hyperuricaemia often complicated by early gout, and tubulointerstitial nephritis that progresses to end-stage renal failure between 30 and 60 years of age. Renal imaging sometimes shows cysts of variable size and number; histology reveals interstitial fibrosis, atrophic tubules, and irregularly thickened tubular membranes. The clinical presentation is insidious — early polyuria and polydipsia are easily overlooked because urinalysis is relatively normal and there is no proteinuria, azotaemia, or hypertension. Most patients are not diagnosed until renal failure has already developed.
Allopurinol is recommended from the early stages of the disease, but its efficacy in slowing progression is not proven. No quantitative data on survival, response rates, or sample sizes from controlled trials are provided in these abstracts. The genetic basis is heterogeneous: mutations in the uromodulin gene (which encodes Tamm-Horsfall protein) are found in fewer than half of families, most often affecting a cysteine in exon 4 and causing abnormal protein retention in the endoplasmic reticulum of Henle loop cells with reduced urinary excretion. At least two other genes — TCF2 and the renin gene — have been implicated in similar clinical presentations. A 2002 study mapped the disease to chromosome 16p12 in six families, but the abstract gives no further details on the gene identified or on any therapeutic implications.
The pathophysiology remains uncertain. Tamm-Horsfall protein’s functions are poorly understood; knockout mice do not develop a renal phenotype but are more prone to E. coli urinary infections. Uromodulin mutations are also found in medullary cystic kidney disease, and the two disorders are now considered facets of the same uromodulin-associated kidney disease. What is still missing is any proven disease-modifying treatment — allopurinol’s effect is uncertain — as well as well-designed prospective trials, patient stratification by genotype, and a clearer understanding of how uromodulin dysfunction leads to progressive fibrosis. Funding for such trials and for basic research into the protein’s role in the kidney remains inadequate.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Clinical Pediatrics · 1986 · 26 citations
Familial Juvenile Nephronophthisis
AbstractFamilial juvenile nephronophthisis (FJN) is a frequent cause of chronic renal failure in children and adolescents. Typically it presents after 6 years of age through adolescence, but may become apparent in early childhood. The clinical presentation is insidious, and the early symptoms of polyuria and polydipsia are often overlooked in the presence of a relatively normal urinalysis and in the absence of proteinuria, azotemia, and hypertension. Thus most patients are not diagnosed until after the onset of renal failure. These children are excellent candidates for properly selected transplantation.
AbstractLa néphropathie hyperuricémique familiale juvénile est une pathologie héréditaire rare se transmettant sur le mode autosomique dominant. Elle se caractérise par un défaut d’excrétion des urates responsable d’une hyperuricémie souvent compliquée de goutte précoce. L’atteinte rénale est une néphropathie tubulo-interstitielle. L’imagerie montre parfois des kystes en taille et nombre variables. La biopsie rénale bien que peu spécifique met en évidence une fibrose interstitielle parfois inflammatoire, des îlots de tubes atrophiques parfois dilatés et aux parois irrégulièrement festonnées. L’insuffisance rénale évolue progressivement vers le stade terminal entre 30 et 60 ans. Le traitement par allopurinol est recommandé dès les stades précoces de la maladie, son efficacité sur le ralentissement de la maladie est incertaine. Il existe une hétérogénéité génétique dans cette maladie. Seul le gène uromoduline codant pour la protéine de Tamm-Horsfall a jusqu’ici pu être mis en cause dans moins de la moitié des familles. Les mutations décrites touchent le plus souvent une cystéine au sein de l’exon 4 entraînant une rétention de la protéine anormale dans le reticulum endoplasmique des cellules de l’anse de Henlé et une diminution de son excrétion urinaire. La physiopathologie de la maladie est encore incertaine. Les fonctions de la protéine de Tamm-Horsfall sont mal connues (rôles anti-infectieux, antilithiasique, immunomodulateur). Les souris knock-out ne développent pas de phénotype rénal mais sont plus sujettes aux infections urinaires à E. Coli. Des mutations du gène de l’uromoduline ont également été mises en évidence dans la maladie kystique de la médullaire, néphropathie tubulo-interstitielle autosomique dominante longtemps distinguée de la néphropathie hyperuricémique familiale juvénile. La génétique a permis de considérer ces deux entités comme les facettes d’une même maladie qu’il conviendrait d’appeler néphropathie associée à l’uromoduline. Au moins deux autres gènes ont été impliqués dans des tableaux cliniques similaires : TCF2 et le gène codant pour la rénine. Familial juvenile hyperuricemic nephropathy is a rare autosomal dominant disease. It is characterized by abnormal handling of urate responsible for hyperuricaemia often complicated of gouty arthritis. Renal failure is due to tubulointerstitial nephritis. Ultrasonography sometimes finds renal cysts of variable size and number. Renal histology, although not specific, shows interstitial fibrosis, atrophic tubules, sometimes enlarged and with irregular membrane thickening. Renal failure progresses to end stage between 30 and 60 years of age. Allopurinol treatment is recommended at the early stages of the disease, its efficacy on slowing down the progression of the disease is however not proven. There is genetic heterogeneity in familial juvenile hyperuricemic nephropathy. Uromodulin encoding Tamm-Horsfall protein is the only gene to date identified, responsible in less than half of the families. The described mutations most often concern a cystein and are clustering in exon 4. These mutations result in abnormal retention of the protein in endoplasmic reticulum of Henle loop cells and in reduction of its urinary excretion. The pathophysiology of the disease is however still dubious. Indeed, Tamm-Horsfall protein functions are not well known (anti-infectious role, cristallisation inhibition, immunomodulating role). Knock-out mice do not develop renal phenotype but are more prone to E. coli urinary infections. Uromodulin gene mutations have also been described in medullary cystic kidney disease, an autosomal dominant tubulointerstitial nephropathy, considered at first as a distinct disorder. Genetic progress allowed us to consider familial juvenile hyperuricemic nephropathy and medullary cystic kidney disease as the two facets of a same disease, we should call uromodulin associated kidney diseases. At least two other genes have been implicated in similar clinical presentation: TCF2 and the gene encoding renin.
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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