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UROMODULIN mutations cause familial juvenile hyperuricemic nephropathy
J J O Turner1, J M Stacey, B Harding
1Molecular Endocrinology Group, Nuffield Department of Medicine, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Oxford, OX3 7LD, United Kingdom.
The Journal of Clinical Endocrinology and Metabolism
|March 12, 2003
Summary
Familial juvenile hyperuricaemic nephropathy (FJHN) is caused by mutations in the UROMODULIN gene. This discovery reveals a new role for UROMODULIN in regulating urate metabolism and kidney function.
Area of Science:
- Nephrology
- Genetics
- Metabolic Disorders
Background:
- Gout and hyperuricemia affect 0.2% of the population, stemming from urate overproduction or reduced renal clearance.
- Familial juvenile hyperuricaemic nephropathy (FJHN) is an autosomal dominant disorder featuring hyperuricemia, low urate excretion, and chronic kidney failure.
Purpose of the Study:
- To identify the genetic mechanisms behind reduced urate excretion in FJHN.
- To investigate the UROMODULIN gene as a potential cause of FJHN.
Main Methods:
- Positional cloning studies were performed on five unrelated FJHN families.
- 13 renal expressed genes within the FJHN locus on chromosome 16p11-p13 were analyzed for mutations.
- Sequencing identified heterozygous missense mutations in the UROMODULIN gene.
Main Results:
- Five heterozygous missense mutations (Cys77Tyr, Cys126Arg, Asn128Ser, Cys255Tyr, Cys300Gly) were found in the UROMODULIN gene.
- These mutations altered evolutionarily conserved residues in the UROMODULIN protein.
- UROMODULIN, a glycoprotein, is implicated in urate metabolism.
Conclusions:
- The UROMODULIN gene is identified as the cause of familial juvenile hyperuricaemic nephropathy.
- This research establishes a novel function for UROMODULIN in the regulation of urate metabolism.
- Findings contribute to understanding the genetic basis of hyperuricemia and kidney disease.