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Human Molecular Genetics Advance Access originally published online on October 21, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 24 3369-3384
DOI: 10.1093/hmg/ddg353
© 2003 Oxford University Press

Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export dynamics

Luca Rampoldi1, Gianluca Caridi2, Daniela Santon3, Francesca Boaretto3, Ilenia Bernascone1, Giuseppe Lamorte1, Regina Tardanico4, Monica Dagnino2, Giacomo Colussi5, Francesco Scolari4, Gian Marco Ghiggeri2, Antonio Amoroso3 and Giorgio Casari1,*

1DIBIT, San Raffaele Scientific Institute, 20132, Milan, Italy, 2Laboratory on Pathophysiology of Uremia, G. Gaslini Institute, 16148, Genoa, Italy, 3Genetics Service, Istituto per l'Infanzia Burlo Garofolo, 34137, Trieste, Italy, 4Spedali Civili and University of Brescia, 25123, Brescia, Italy and 5Unita' di Nefrologia, Ospedale di Circolo, 21100, Varese, Italy

Received August 28, 2003; Accepted October 14, 2003

The disease complex medullary cystic disease/familial juvenile hyperuricemic nephropathy (MCKD/FJHN) is characterized by alteration of urinary concentrating ability, frequent hyperuricemia, tubulo-interstitial fibrosis, cysts at the cortico-medullary junction and renal failure. MCKD/FJHN is caused by mutations of the gene encoding uromodulin, the most abundant protein in urine. Here, we describe new missense mutations in three families with MCKD/FJHN and demonstrate allelism with a glomerulocystic kidney disease (GCKD) variant, showing association of cyst dilatation and collapse of glomeruli with some clinical features similar to MCKD/FJHN as hyperuricemia and impairment of urine concentrating ability. Furthermore, we provide the first functional characterization of uromodulin mutations. The four newly identified mutants were characterized by immunofluorescence and FACS analysis on transfected cells. These experiments showed that all uromodulin mutations cause a delay in protein export to the plasma membrane due to a longer retention time in the endoplasmic reticulum. Immunohistochemistry on GCKD and MCKD/FJHN kidney biopsies revealed dense intracellular accumulation of uromodulin in tubular epithelia of the thick ascending limb of Henle's loop. Electron microscopy demonstrated accumulation of dense fibrillar material within the endoplasmic reticulum. Consistently, patient urines show a severe reduction of excreted uromodulin. The maturation impairment is consistent with the clinical findings and suggests a pathogenetic mechanism leading to these kidney diseases.

* To whom correspondence should be addressed at: Human Molecular Genetics Unit, DIBIT-San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. Tel: +39 0226433502; Fax: +39 0226434767; Email: casari.giorgio{at}hsr.it


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