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

Abstract

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.

A structured interdomain linker directs self-polymerization of human uromodulin

“…2B) and is absent in ZP3 (3,5). Loss of either Cys is also associated with ADTKD, due to intracellular aggregation and impaired urinary secretion of UMOD (22,23) (Fig. S3 and Table S2).…”

Uromodulin: old friend with new roles in health and disease

“…Mutations in separate domains of the UMOD gene may result in similar clinical phenotypes and, conversely, seemingly identical mutations may lead to any of the three phenotypes [15,35], suggesting that other modifying genetic or environmental factors play a role. This notion is supported by the demonstration of wide intrafamilial variation in the severity of UAKD [21].…”

Abnormal expression and processing of uromodulin in Fabry disease reflects tubular cell storage alteration and is reversible by enzyme replacement therapy

“…In these patients UMOD mutations led to intracellular UMOD accumulation, absence of the protein on the plasma membrane and decreased urinary excretion (Bernascone et al 2006;Bleyer et al 2004;Dahan et al 2003;Hodanova et al 2005;Rampoldi et al 2003;Vylet_al et al 2006). Changes in UMOD expression, cellular localization and urinary excretion were found also in FJHN/MCKD patients with no UMOD mutation and this led to introduction of the term Furomodulin-associated kidney diseases_ (UAKD) (Hart et al 2002;Hodanova et al 2005;Vylet_al et al 2006).…”