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J Am Soc Nephrol 14:2883-2893, 2003
© 2003 American Society of Nephrology

CLINICAL SCIENCE

A Cluster of Mutations in the UMOD Gene Causes Familial Juvenile Hyperuricemic Nephropathy with Abnormal Expression of Uromodulin

Karin Dahan*, Olivier Devuyst{dagger}, Michèle Smaers*, Didier Vertommen{dagger}, Guy Loute§, Jean-Michel Poux||, Béatrice Viron, Christian Jacquot#, Marie-France Gagnadoux**, Dominique Chauveau{dagger}{dagger}, Mathias Büchler{ddagger}{ddagger}, Pierre Cochat§§, Jean-Pierre Cosyns||||, Béatrice Mougenot¶¶, Mark H. Rider{ddagger}, Corinne Antignac##, Christine Verellen-Dumoulin* and Yves Pirson{dagger}

*Université Catholique de Louvain, Center for Human Genetics, Brussels, Belgium; {dagger}Université Catholique de Louvain, Division of Nephrology, Brussels, Belgium; {ddagger}Université Catholique de Louvain, International Institute of Cellular and Molecular Pathology, HORM Unit, Brussels, Belgium; §Hôpital Princesse Paola, Department of Nephrology, Aye, Belgium; ||Hôpital de Frejus, Department of Nephrology, Frejus, France; Hôpital Bichat-Claude Bernard, Department of Nephrology, Paris, France; #Hôpital Georges Pompidou, Department of Nephrology, Paris, France; **Hôpital Necker, Department of Pediatric Nephrology, Paris, France; {dagger}{dagger}Hôpital Necker, Department of Nephrology and INSERM U507, Paris, France; {ddagger}{ddagger}Centre Hospitalier Régional, Department of Nephrology, Tours, France; §§Hôpital Edouard Herriot, Department of Pediatric Nephrology, Lyon, France; ||||Université Catholique de Louvain, Department of Pathology, Brussels, Belgium; ¶¶Hôpital Tenon, Department of Pathology, Paris, France; and ##Université Paris V, Necker Hospital, INSERM U574, and Department of Genetics, Paris, France

Correspondence to Dr. Karin Dahan, Center for Human Genetics, Université Catholique de Louvain, Avenue E. Mounier 52, Tour Vésale 5220, B-1200, Brussels, Belgium. Phone: 0032-2-764-52-20; Fax: 0032-2-764-52-22;

ABSTRACT. 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. E-mail: Dahan@gmed.ucl.ac.be




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