Uromodulin storage diseases: Clinical aspects and mechanisms

Università degli Studi di Trieste, Trst, Friuli Venezia Giulia, Italy
American Journal of Kidney Diseases (Impact Factor: 5.9). 01/2005; 44(6):987-99. DOI: 10.1053/j.ajkd.2004.08.021
Source: PubMed


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.

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    • "Uromodulin gene (UMOD) mutations have been confirmed in patients with familial juvenile hyperuricemia nephropathy (FJHN, OMIM 162000), medullary cystic kidney disease 2 (MCKD2, OMIM 603860) and glomerulocystic kidney disease (GCKD, OMIM 609886). Hyperuricemia, hypertension, decreased urinary uromodulin levels, tubulointerstitial nephropathy and progressive kidney disease are characteristics of these diseases [3], [4]. Genome-wide association studies have also revealed that common variants in the promoter region of the UMOD gene are associated with chronic kidney disease (CKD), glomerular filtration rate (GFR), kidney stone formation and hypertension [5], [6], [7], [8]. "
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    ABSTRACT: Uromodulin, or Tamm-Horsfall protein, is the most abundant urinary protein in healthy individuals. Recent studies have suggested that uromodulin may play a role in chronic kidney diseases. We examined an IgA nephropathy cohort to determine whether uromodulin plays a role in the progression of IgA nephropathy. A total of 344 IgA nephropathy patients were involved in this study. Morphological changes were evaluated with the Oxford classification of IgA nephropathy. Enzyme Linked Immunosorbent Assay (ELISA) measured the urinary uromodulin level on the renal biopsy day. Follow up was done regularly on 185 patients. Time-average blood pressure, time-average proteinuria, estimated glomerular filtration rate (eGFR) and eGFR decline rate were caculated. Association between the urinary uromodulin level and the eGFR decline rate was analyzed with SPSS 13.0. We found that lower baseline urinary uromodulin levels (P = 0.03) and higher time-average proteinuria (P = 0.04) were risk factors for rapid eGFR decline in a follow-up subgroup of the IgA nephropathy cohort. Urinary uromodulin level was correlated with tubulointerstitial lesions (P = 0.016). Patients that had more tubular atrophy/interstitial fibrosis on the surface had lower urinary uromodulin levels (P = 0.02). Urinary uromodulin level is associated with interstitial fibrosis/tubular atrophy and contributes to eGFR decline in IgA nephropathy.
    Full-text · Article · Aug 2013 · PLoS ONE
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    • "Uromodulin mutations are found to be associated with three autosomal dominant conditions, namely familial juvenile hyperuricemic nephropathy (FJHN1; MIM 162000); medullary cystic kidney disease type 2 (MIM 603860), and glomerulocystic kidney disease (MIM 609886) [2,3,4]. The majority of UMOD mutations cluster in exons 4.5 and 8 [5] and cause replacement of cysteine residues, leading to misfolding of the uromodulin molecule, with the abnormal uromodulin becoming entrapped in the endoplasmatic reticulum of the cells of the thick ascending limb of the loop of Henle. "
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    ABSTRACT: Uromodulin-associated kidney disease (UAKD) is caused by uromodulin mutations and leads to end-stage renal disease. Our objective was to examine the epidemiology of UAKD. Data from all UAKD families in Austria were collected. Patients included in the Austrian Dialysis and Transplantation Registry (OEDTR) with unclear diagnoses or genetic diseases were asked whether they had (1) a family history of kidney disease or (2) had suffered from gout. Patients with gout and autosomal dominant renal disease underwent mutational analysis. Kaplan-Meier and Cox analysis was employed to estimate time to renal failure. Of the 6,210 patients in the OEDTR, 541 were approached with a questionnaire; 353 patients answered the questionnaire. Nineteen of them gave two affirmative answers. In 7 patients, an autosomal dominant renal disease was found; in 1 patient a UMOD mutation was identified. One family was diagnosed through increased awareness as a consequence of the study. At present, 14 UAKD patients from 5 families are living in Austria (1.67 cases per million), and 6 of them require renal replacement therapy (0.73 per 1,000 patients). Progression to renal failure was significantly associated with UMOD genotype. UAKD patients can be identified by a simple questionnaire. UMOD genotype may affect disease progression.
    Full-text · Article · Jun 2012
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    • "But two of seven families were found not to be linked to chromosome 16p11-p13, thereby demonstrating genetic heterogeneity in more than 25% of FJHN families (8). Its clinical and histologic features are similar to those of MCKD type 2. Recent genetic studies revealed that MCKD type 2 is also associated with mutations in the UMOD gene, therefore an opinion is emerging that FJHN and MCKD type 2 are not the different diseases (9). "
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    ABSTRACT: Familial Juvenile hyperuricemic nephropathy (FJHN, OMIM #162000) is a rare autosomal dominant disorder characterized by hyperuricemia with renal uric acid under-excretion, gout and chronic kidney disease. In most but not all families with FJHN, genetic studies have revealed mutations in the uromodulin (UMOD) gene located on chromosome 16p11-p13. We here described a novel heterozygous missense mutation (c.1382C>A causing p.Ala461Glu) in an affected 16-year-old male with hyperuricemia, gout and chronic kidney disease. His father was also affected and the UMOD mutation was found to segregate with the disease. There has been only one case report of Korean family with FJHN, which has not been diagnosed by genetic study. This is the first report of genetically diagnosed FJHN in Korea.
    Full-text · Article · Nov 2010 · Journal of Korean medical science
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