Human Molecular Genetics Advance Access published online on October 21, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg353
© 2003 by Oxford University Press
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1 DIBIT, San Raffaele Scientific Institute, 20132, Milan, Italy
* To whom correspondence should be addressed. E-mail: casari.giorgio{at}hsr.it.
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.
Article
Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export dynamics
2 Laboratory on Pathophysiology of Uremia, G. Gaslini Institute, 16148, Genoa, Italy
3 Genetics Service, Istituto per l'Infanzia Burlo Garofolo, 34137, Trieste, Italy
4 Spedali Civili and University of Brescia, 25123, Brescia, Italy
5 Unita' di Nefrologia, Ospedale di Circolo, 21100, Varese, Italy
6 Human Molecular Genetics Unit, DIBIT-San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy
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