Alterations of uromodulin biology: a common denominator of the genetically heterogeneous FJHN/MCKD syndrome

Abstract

Autosomal dominant hyperuricemia, gout, renal cysts, and progressive renal insufficiency are hallmarks of a disease complex comprising familial juvenile hyperuricemic nephropathy and medullary cystic kidney diseases type 1 and type 2. In some families the disease is associated with mutations of the gene coding for uromodulin, but the link between the genetic heterogeneity and mechanism(s) leading to the common phenotype symptoms is not clear. In 19 families, we investigated relevant biochemical parameters, performed linkage analysis to known disease loci, sequenced uromodulin gene, expressed and characterized mutant uromodulin proteins, and performed immunohistochemical and electronoptical investigation in kidney tissues. We proved genetic heterogeneity of the disease. Uromodulin mutations were identified in six families. Expressed, mutant proteins showed distinct glycosylation patterns, impaired intracellular trafficking, and decreased ability to be exposed on the plasma membrane, which corresponded with the observations in the patient's kidney tissue. We found a reduction in urinary uromodulin excretion as a common feature shared by almost all of the families. This was associated with case-specific differences in the uromodulin immunohistochemical staining patterns in kidney. Our results suggest that various genetic defects interfere with uromodulin biology, which could lead to the development of the common disease phenotype. 'Uromodulin-associated kidney diseases' may be thus a more appropriate term for this syndrome.

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

“…Attenuated UMOD expression is thus probably linked directly to the lysosomal storage process. Similar decrease in UMOD transcription and expression was found recently in mice with renal-specific inactivation of HNF1b (Gresh et al 2004), Brn1 j/j mice (Nakai et al 2003), an ischaemia-reperfusion model of ARF in rat (Yoshida et al 2002), in some patients with UAKD (Hodanova et al 2005;Vylet_al et al 2006), and in kidney damage (Chakraborty et al 2004).…”

“…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).…”

No Amelioration of Uromodulin Maturation and Trafficking Defect by Sodium 4-Phenylbutyrate in Vivo

“…MTCs do not express endogenous uromodulin protein but provide the maturation capacity for GPI-linked secreted proteins thereby facilitating the interpretation of maturation ability of the mutant protein. (3,(12)(13)(14)34). However, these in vitro models were described to be not suitable to analyze potential disease mechanisms downstream of mutant uromodulin retention as the cellular models reported so far did not reproduce key cellular hallmarks of UAKD, which are mutant uromodulin aggregation, ER membrane expansion, and ER dilation (4).…”

“…ER retention of mutated UMOD is considered as a key step in the pathogenesis of UAKD (4). Analyses of kidney biopsies of UAKD patients revealed a hyperplastic ER in TALH cells with overexpression of BiP and PDI, indicative of ER stress (8,14,15). ER hyperplasia and activation of ER-resident molecular chaperones (e.g.…”

Tamm Horsfall Glycoprotein and Uromodulin

“…Mutations in the UMOD gene result in improper crosslinking of the molecule and the inability of uromodulin to achieve its normal configuration. Abnormal uromodulin polymerizes within renal tubular cells (8,9), leading to accelerated tubular cell death, nephron loss, and progressive kidney disease.…”