Uromodulin storage diseases: Clinical aspects and mechanisms

Abstract

• The recent discovery of mutations in the uromodulin gene (UMOD) in patients with medullary cystic kidney disease type 2 (MCKD2), familial juvenile hyperuricemic nephropathy (FJHN), and glomerulocystic kidney disease (GCKD) provides the opportunity for a revision of pathogenic aspects and puts forth the basis for a renewed classification. This review focuses on clinical, pathological, and cell biology advances in UMOD-related pathological states, including a review of the associated clinical conditions described to date in the literature. Overall, 31 UMOD mutations associated with MCKD2 and FJHN (205 patients) and 1 mutation associated with GCKD (3 patients) have been described, with a cluster at exons 4 and 5. Most are missense mutations causing a cysteine change in uromodulin sequence. No differences in clinical symptoms between carriers of cysteine versus polar residue changes have been observed; clinical phenotypes invariably are linked to classic MCKD2/FJHN. A common motif among all reports is that many overlapping symptoms between MCKD2 and FJHN are present, and a separation between these 2 entities seems unwarranted or redundant. Cell experiments with mutant variants indicated a delay in intracellular maturation and export dynamics, with consequent uromodulin storage within the endoplasmic reticulum (ER). Patchy uromodulin deposits in tubule cells were found by means of immunohistochemistry, and electron microscopy showed dense fibrillar material in the ER. Mass spectrometry showed only unmodified uromodulin in urine of patients with UMOD mutations. Lack of uromodulin function(s) is associated with impairments in tubular function, particularly the urine-concentrating process, determining water depletion and hyperuricemia. Intracellular uromodulin trapping within the ER probably has a major role in determining tubulointerstitial fibrosis and renal failure. We propose the definition of uromodulin storage diseases for conditions with proven UMOD mutations. Am J Kidney Dis 44:987-999.

Clinical, Genetic, and Urinary Factors Associated with Uromodulin Excretion

“…Noteworthy, hyperuricemia is caused by a decreased FE-Ua, which appears early and precedes the decline in renal function (6). It has been hypothesized that defective reabsorption of NaCl in the TAL may lead to volume contraction and a secondary increase in proximal tubule reabsorption of Ua (31). Of note, uromodulin knockout mice display a reduced NKCC2 cotransporter phosphorylation, whereas overexpression of uromodulin in vitro increases NKCC2 phosphorylation (11).…”

Phenotype and Outcome in Hereditary Tubulointerstitial Nephritis Secondary to UMOD Mutations

“…Clinicians identified several phenotypes that appeared to be distinct and labeled these as familial juvenile hyperuricemic nephropathy (FJHN), medullary cyst kidney disease (MCKD), or adult nephronophthisis, all of autosomal dominant inheritance (1).…”

Mutant Tamm-Horsfall Glycoprotein Accumulation in Endoplasmic Reticulum Induces Apoptosis Reversed by Colchicine and Sodium 4-Phenylbutyrate

“…M utations in the uromodulin (UMOD) gene result in an autosomal dominantly transmitted syndrome characterized by precocious hyperuricemia, gout, and progressive kidney failure frequently leading to dialysis (1)(2)(3). This condition has been termed familial juvenile hyperuricemic nephropathy (FJHN), medullary cystic kidney disease type 2 (MCKD-2), and glomerulocystic kidney disease (2,4).…”

“…This condition has been termed familial juvenile hyperuricemic nephropathy (FJHN), medullary cystic kidney disease type 2 (MCKD-2), and glomerulocystic kidney disease (2,4). Most UMOD mutations involve alteration of highly conserved cysteine residues that compromise processing of uromodulin/ Tamm Horsfall glycoprotein (THP) (3,5). Uromodulin and THP are two large glycoproteins with an identical amino acid sequence, and both are a product of the UMOD gene.…”