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

Luca Rampoldi, Gianluca Caridi, Daniela Santon, Francesca Boaretto, Ilenia Bernascone, Giuseppe Lamorte, Regina Tardanico, Monica Dagnino, Giacomo Colussi, Francesco Scolari, Gian Marco Ghiggeri, Antonio Amoroso, Giorgio Casari

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)3369-3384
Number of pages16
JournalHuman Molecular Genetics
Issue number24
Publication statusPublished - Dec 15 2003

ASJC Scopus subject areas

  • Genetics


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