BES2003 Poster Presentations Diabetes, Metabolism and Cardiovascular (35 abstracts)
Identification of the gene causing familial juvenile hyperuricaemic (Gouty) nephropathy
JM Stacey 1 , JJO Turner 1 , B Harding 1 , P Kotanko 2 , K Lhotta 3 , JG Puig 4 , I Roberts 5 , RJ Torres 4 & RV Thakker 1
1Molecular Endocrinology Group, Nuffield Department of Medicine, Botnar Research Centre, University of Oxford, Oxford, UK; 2Department of Internal Medicine, Krankenhaus der Barmherzigen Brueder (Teaching Hospital KFU Graz), Graz, Austria; 3Department of Clinical Nephrology, Innsbruck University Hospital, Austria; 4Servicio de Medicina Interna, Hospital General, Madrid, Spain; 5Department of Histopathology, John Radcliffe Hospital, Oxford, UK.
Gout, which is commonly associated with hyperuricaemia, affects 0.2% of the population. Hyperuricaemia has a heterogeneous aetiology 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 characterised by hyperuricaemia, a low fractional renal excretion of urate and chronic renal failure that is associated with interstitial fibrosis. The gene causing FJHN, also know as familial juvenile gouty nephropathy (FJGN), is located on chromosome 16p11-p13. We first pursued linkage studies in 5 families (containing 21 affected and 24 unaffected members) using eleven chromosome 16p11-p13 polymorphic loci whose order has been established as 16pter - D16S3069-D16S3060-D16S3041-D16S3036-D16S3046-[D16S403,D16S417]-D16S420-D16S3113-D16S401-D16S3133-16cen. Linkage was established between FJHN and six loci (peak LOD score= 5.32 with D16S417, at 0% recombination), with the most likely location of FJHN being within the 22 centiMorgan (cM) interval flanked by D16S401 and D16S3069. Analysis of the Ensembl, Marshfield, Cedar Genetics and UDB maps revealed this interval to contain over 120 genes and we undertook a prioritised mutational analysis program of sequences that were known to be renally expressed. Analysis of the twentieth gene revealed sequence abnormalities that altered evolutionary conserved cysteine residues (Cys to Tyr, Cys to Gly and Cys to Arg), in 3 of the 5 FJHN families. Cosegregation of these abnormalities was demonstrated and their absence from 110 alleles of 55 unrelated normals confirmed that they were mutations and not common DNA sequence polymorphisms. The gene harbouring these mutations encodes a <100 kDa protein whose function in urate metabolism remains to be defined. Thus, our studies have identified the gene causing familial juvenile hyperuricaemic (gouty) nephropathy and this will help to elucidate further the mechanisms controlling urate homeostasis.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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