Genome-wide study of familial juvenile hyperuricaemic (gouty) nephropathy (FJHN) indicates a new locus, FJHN3, linked to chromosome 2p22.1-p21.
Familial juvenile hyperuricaemic (gouty) nephropathy (FJHN), is an autosomal dominant disease associated with a reduced fractional excretion of urate, and progressive renal failure. FJHN is genetically heterogeneous and due to mutations of three genes: uromodulin (UMOD), renin (REN) and hepatocyte nuclear factor-1beta (HNF-1β) on chromosomes 16p12, 1q32.1, and 17q12, respectively. However, UMOD, REN or HNF-1β mutations are found in only approximately 45% of FJHN probands, indicating the involvement of other genetic loci in approximately 55% of probands. To identify other FJHN loci, we performed a single nucleotide polymorphism (SNP)-based genome-wide linkage analysis, in six FJHN families in whom UMOD, HNF-1β and REN mutations had been excluded. Parametric linkage analysis using a 'rare dominant' model established linkage in five of the six FJHN families, with a LOD score >+3, at 0% recombination, between FJHN and SNPs at chromosome 2p22.1-p21. Analysis of individual recombinants in two unrelated affected individuals defined a approximately 5.5 Mbp interval, flanked telomerically by SNP RS372139 and centromerically by RS896986 that contained the locus, designated FJHN3. The interval contains 28 genes, and DNA sequence analysis of the most likely candidate, solute carrier family 8 member 1 (SLC8A1), did not identify any abnormalities in the FJHN3 probands. FJHN3 is likely located within a approximately 5.5 Mbp interval on chromosome 2p22.1-p21, and identifying the genetic abnormality will help to further elucidate mechanisms predisposing to gout and renal failure.
Academic Endocrine Unit, Oxford Centre for Diabetes Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Headington, Oxford, OX3 7LJ, UK.
Sian E
SE
Piret
Patrick
P
Danoy
Karin
K
Dahan
Anita A C
AA
Reed
Karena
K
Pryce
William
W
Wong
Rosa J
RJ
Torres
Juan G
JG
Puig
Thomas
T
Müller
Peter
P
Kotanko
Karl
K
Lhotta
Olivier
O
Devuyst
Matthew A
MA
Brown
Rajesh V
RV
Thakker
D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D005260:Female; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006073:Gout / Q000235:genetics; D006801:Humans; D033461:Hyperuricemia / Q000235:genetics; D007674:Kidney Diseases / Q000235:genetics; D007676:Kidney Failure, Chronic / Q000235:genetics; D008297:Male; D010375:Pedigree; D014527:Uric Acid / Q000097:blood / Q000378:metabolism
D014527:Uric Acid