title: UROMODULIN mutations cause familial juvenile hyperuricemic nephropathy.
abstract: Gout, which is commonly associated with hyperuricemia, affects 0.2% of the population. Hyperuricemia has a heterogeneous etiology that may be due to either over production and/or reduced renal clearance, of urate. In order to identify the mechanisms underlying reduced excretion of urate, we undertook positional cloning studies of familial juvenile hyperuricaemic nephropathy (FJHN), which is an autosomal dominant disorder characterized by hyperuricaemia, a low fractional renal excretion of urate, and chronic renal failure that is associated with interstitial fibrosis. The FJHN locus has been previously localized to a 22 centiMorgan interval flanked centromerically by D16S401 and telomerically by D16S3069, on chromosome 16p11-p13. This interval contains over 120 genes and we selected 13 renal expressed sequences to search for mutations in 5 unrelated FJHN families that contained 21 affected and 24 unaffected members. This revealed 5 heterozygous missense mutations (Cys77Tyr, Cys126Arg, Asn128Ser, Cys255Tyr and Cys300Gly) that altered evolutionary conserved residues in the gene encoding UROMODULIN. UROMODULIN, which is an 85 Kda glycoprotein, has roles in renal stone formation, the modulation of immune responses, and urothelial cytoprotection. The results of our studies, which have identified the gene causing FJHN, now indicate a further, novel role for UROMODULIN in urate metabolism.
authors.affiliation: Molecular Endocrinology Group, Nuffield Department of Medicine, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Oxford, OX3 7LD, United Kingdom.
authors.forename: J J O
authors.initials: JJ
authors.lastname: Turner
authors.forename: J M
authors.initials: JM
authors.lastname: Stacey
authors.forename: B
authors.initials: B
authors.lastname: Harding
authors.forename: P
authors.initials: P
authors.lastname: Kotanko
authors.forename: K
authors.initials: K
authors.lastname: Lhotta
authors.forename: J G
authors.initials: JG
authors.lastname: Puig
authors.forename: I
authors.initials: I
authors.lastname: Roberts
authors.forename: R J
authors.initials: RJ
authors.lastname: Torres
authors.forename: R V
authors.initials: RV
authors.lastname: Thakker
mesh_terms: D000595:Amino Acid Sequence; D000071837:Fibrillins; D006801:Humans; D033461:Hyperuricemia / Q000235:genetics*; D007674:Kidney Diseases / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009088:Mucoproteins / Q000235:genetics*; D009154:Mutation; D058949:Uromodulin
chemical_list: D000071837:Fibrillins; D008840:Microfilament Proteins; D009088:Mucoproteins; C548612:UMOD protein, human; D058949:Uromodulin