DeCure for Familial juvenile hyperuricemic nephropathy type 2
DeCure's autonomous Nephrology AI scientist is researching a drug-repurposing hypothesis for familial juvenile hyperuricemic nephropathy type 2 — 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 moduleFamilial juvenile hyperuricemic nephropathy type 2 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 familial juvenile hyperuricemic nephropathy type 2 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
renin (REN) — REN 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 2-bromo-5-fluorophenoxydrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3K1W · 1.5 Å · ligand 4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-N-(2-chlorobenzyl)-N-cyclopropyl-1,2,5,6-tetrahydropyridine-3-carboxamide (BFX). Experimental structure, not a prediction.
What the evidence adds up to
Familial juvenile hyperuricemic nephropathy type 2 is caused by mutations in the uromodulin (UMOD) gene, as reported in 2002 and 2003. The 2003 letter describes three kindreds with UMOD mutations and an additional family identified subsequently; two other groups confirmed the finding. Uromodulin, also known as Tamm-Horsfall glycoprotein, is produced in the thick ascending limb of Henle, not in the proximal tubule where most uric acid transport occurs, and its function remains unclear. The same 2003 letter states that not all individuals with a UMOD mutation have hyperuricaemia: several patients with a mutation had progressive renal failure despite normal serum uric acid levels. Several family members also had progressive renal disease despite using allopurinol. The authors conclude that hyperuricaemia in these families is secondary to functional changes from the UMOD mutation, not the primary disorder, and that allopurinol does not stop progression. Whether it slows progression is difficult to determine because sample sizes in all studied groups are small.
A 2013 case report describes a sixteen-year-old boy referred for a strong family history of renal disease. His mother and maternal aunt had end-stage renal disease, two maternal cousins had chronic kidney disease, and all affected members had hyperuricaemia. Renal ultrasounds showed unilateral renal hypoplasia in the index case, his mother, and his aunt. Two affected cousins had normal-sized kidneys, suggesting a modifier gene effect. Affected members tested negative for mutations in UMOD and in hepatocyte nuclear factor 1β (HNF1b), two major genes implicated in familial juvenile hyperuricemic nephropathy. The authors note this is the first report of unilateral renal hypoplasia inherited in an autosomal dominant manner in this disease.
A 2002 conference abstract reports mapping of familial juvenile hyperuricemic nephropathy to chromosome 16p12 in six families. A 2005 paper provides a sequence image of an index patient with an exon 5 c.920A→C heterozygous mutation in UMOD. The 1986 paper on familial juvenile nephronophthisis, a different disease, describes it as a frequent cause of chronic renal failure in children and adolescents, presenting insidiously after age six with polyuria and polydipsia, often diagnosed only after renal failure onset, and notes these children are candidates for transplantation.
What is still missing: larger, genetically stratified studies to determine whether allopurinol or any other urate-lowering drug slows renal progression in any UMOD-mutation subgroup; identification of other genes that may cause the phenotype in families without UMOD or HNF1b mutations; and prospective trials that account for the variable penetrance of hyperuricaemia and renal hypoplasia.
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.
AbstractSir, We would like to take this opportunity to provide some updated information regarding the pathogenesis of familial juvenile hyperuricaemic nephropathy (FJHN). There has been discussion in recent months in QJM as to whether hyperuricaemia is a primary or secondary effect of the disease.1,2 In a Letter to the Editor from QJM, February 2003,1 it was stated by Drs Puig and Torres that an ‘ … unresolved aspect of FJHN is the gene defect.’ In December 2002, we reported mutation in the uromodulin gene as a cause of FJHN in three kindreds.3 We then identified an additional family with a mutation in the uromodulin gene as a cause of FJHN.4 Two other groups have subsequently confirmed our original report.5,6 While there is speculation that other genes may be responsible for this condition, no other genes have as yet been identified. Uromodulin, better known as Tamm-Horsfall glycoprotein, is produced in the thick ascending limb of Henle.7 Despite many years of study, the function of Tamm-Horsfall protein remains unclear. It has been postulated to be important in main-taining the integrity of the thick ascending loop of Henle,8 binding to various cytokines,9 or preventing urinary tract infections.10 It has not been postulated to be involved in uric acid transport, and this would seem unlikely, as most uric acid transport occurs in the proximal tubule, and Tamm-Horsfall glycoprotein is localized to later portions of the tubule. Identification of uromodulin mutations associated with FJHN has permitted us to definitively identify all mutation carriers in a given family, allowing us to characterize the variability in clinical presentation of the disease. Through studies of genotype-phenotype correlations in families segregating FJHN causing uromodulin gene mutations, we have been able to determine that not all individuals suffering from FJHN have hyperuricaemia.11 Several of our patients carrying a uromodulin gene mutation have suffered from progressive renal failure, despite having normal serum uric acid levels. Several family members have also had progressive renal disease despite the usage of allopurinol. These results suggest that the hyperuricemia associated with FJHN is secondary to functional changes brought about by the mutation in the uromodulin gene, and that hyperuricaemia is not the primary disorder. In our experience, allopurinol does not stop progression, but whether it slows progression is difficult to determine, due to small sample sizes in all groups studied so far. It is possible that other mutations may result in a clinical phenotype presenting as FJHN. For this reason, in order to prevent confusion, we suggest the term ‘uromodulin-associated kidney disease’ for those families with a uromodulin gene mutation. With regard to allopurinol responsiveness, families with a mutation in the uromodulin gene may not be responsive to allopurinol, whereas families with a mutation in other genes may be responsive. To this end, it would be most useful to know if uromodulin mutations are responsible for FJHN in the families reported by Puig and Fairbanks.1,2
Archives of Disease in Childhood · 2013 · 0 citations · open access
G65(P) Unilateral Hypoplastic Kidney - a Novel and Highly Penetrant Feature of Familial Juvenile Hyperuricaemic Nephropathy
Abstract<h3>Aim</h3> To highlight an interesting and novel renal phenotype that may provide an insight into the genetics surrounding the development of isolated renal hypoplasia. <h3>Methods</h3> A sixteen year old boy was referred to Paediatric Nephrology services following concerns of a strong family history of renal disease. Both his mother and maternal aunt have end stage renal disease. Two of his maternal cousins were found to have chronic kidney disease. All affected members had evidence of hyperuricaemia. The patient’s grandparents and maternal uncles were not affected. Renal ultrasounds performed on affected family members revealed unilateral renal hypoplasia in the index case, as well as his mother and aunt. <h3>Results</h3> Our case report describes a pedigree with familial juvenile hyperuricaemic nephropathy, a relatively uncommon condition characterised by hypoexcretion of urate leading to hyperuricaemia, gout and progressive renal impairment. This family, however, require our attention for several reasons. Firstly, three affected family members demonstrate unilateral renal hypoplasia inherited in an autosomal dominant manner: to our knowledge this is the first report to describe such a phenotype. Secondly, two affected cousins had normal sized kidneys, suggesting a modifier gene effect, and lastly affected members have tested negative for mutations in two of the major genes implicated in FJHN, which have also been linked to a role in renal morphogenesis: uromodulin (<i>UMOD</i>) and hepatocyte nuclear factor 1β (<i>HNF1b</i>). <h3>Conclusion</h3> Isolated renal hypoplasia is a common congenital anomaly for which a gene association has never been found. The presence of this phenotype in an autosomal dominant manner in this pedigree is therefore of great potential importance, for the ability to identify for the first time a gene responsible for unilateral renal hypoplasia. The association here with renal failure and hyperuricaemia is fascinating, and may provide novel developmental insights linking tubular development, control of lateral renal maturation and renal size. We discuss the known genetics surrounding renal embryogenesis and the implications our pedigree may have for further understanding of this common developmental anomaly.
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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