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.
Dahan
Karin
K
Université Catholique de Louvain, Center for Human Genetics, Brussels, Belgium. Dahan@gmed.ucl.ac.be
Devuyst
Olivier
O
Smaers
Michèle
M
Vertommen
Didier
D
Loute
Guy
G
Poux
Jean-Michel
JM
Viron
Béatrice
B
Jacquot
Christian
C
Gagnadoux
Marie-France
MF
Chauveau
Dominique
D
Büchler
Mathias
M
Cochat
Pierre
P
Cosyns
Jean-Pierre
JP
Mougenot
Béatrice
B
Rider
Mark H
MH
Antignac
Corinne
C
Verellen-Dumoulin
Christine
C
Pirson
Yves
Y
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