A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin.
Familial juvenile hyperuricemic nephropathy (FJHN [MIM 162000]) is an autosomal-dominant disorder characterized by abnormal tubular handling of urate and late development of chronic interstitial nephritis leading to progressive renal failure. A locus for FJHN was previously identified on chromosome 16p12 close to the MCKD2 locus, which is responsible for a variety of autosomal-dominant medullary cystic kidney disease (MCKD2). UMOD, the gene encoding the Tamm-Horsfall/uromodulin protein, maps within the FJHN/MCKD2 critical region. Mutations in UMOD were recently reported in nine families with FJHN/MCKD2 disease. A mutation in UMOD has been identified in 11 FJHN families (10 missense and one in-frame deletion)-10 of which are novel-clustering in the highly conserved exon 4. The consequences of UMOD mutations on uromodulin expression were investigated in urine samples and renal biopsies from nine patients in four families. There was a markedly increased expression of uromodulin in a cluster of tubule profiles, suggesting an accumulation of the protein in tubular cells. Consistent with this observation, urinary excretion of wild-type uromodulin was significantly decreased. The latter findings were not observed in patients with FJHN without UMOD mutations. In conclusion, this study points to a mutation clustering in exon 4 of UMOD as a major genetic defect in FJHN. Mutations in UMOD may critically affect the function of uromodulin, resulting in abnormal accumulation within tubular cells and reduced urinary excretion.
Université Catholique de Louvain, Center for Human Genetics, Brussels, Belgium. Dahan@gmed.ucl.ac.be
Karin
K
Dahan
Olivier
O
Devuyst
Michèle
M
Smaers
Didier
D
Vertommen
Guy
G
Loute
Jean-Michel
JM
Poux
Béatrice
B
Viron
Christian
C
Jacquot
Marie-France
MF
Gagnadoux
Dominique
D
Chauveau
Mathias
M
Büchler
Pierre
P
Cochat
Jean-Pierre
JP
Cosyns
Béatrice
B
Mougenot
Mark H
MH
Rider
Corinne
C
Antignac
Christine
C
Verellen-Dumoulin
Yves
Y
Pirson
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D033461:Hyperuricemia / Q000235:genetics*; D007676:Kidney Failure, Chronic / Q000235:genetics*; D008138:Loop of Henle / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009088:Mucoproteins / Q000235:genetics* / Q000378:metabolism*; D005810:Multigene Family / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D058949:Uromodulin
D009088:Mucoproteins; C548612:UMOD protein, human; D058949:Uromodulin