Mutations of the Uromodulin gene in MCKD type 2 patients cluster in exon 4, which encodes three EGF-like domains

Wolf, Matthias; Mucha, Bettina; Attanasio, Massimo; Zalewski, Isabella; Karle, Stephanie M.; Neumann, Hartmut P. H.; Rahman, Nazneen; Bader, Birgit; Baldamus, C. A.; Otto, Edgar A.; Witzgall, Ralph; Fuchshuber, Arno; Hildebrandt, Friedhelm

doi:10.1046/j.1523-1755.2003.00269.x

Cited by 88 publications

(72 citation statements)

References 24 publications

(35 reference statements)

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“…This finding later was confirmed by other groups [7][8][9][10][11][12][13][14] and recently was extended to autosomal dominant GCKD. 10 Uromodulin (also known as Tamm-Horsfall protein) was found to be accumulating in patch aggregates in all these conditions, suggesting a common pathogenesis.…”

supporting

confidence: 75%

“…[7][8][9][10][11][12][13][14] UMOD mutations also were reported in a family with autosomal dominant GCKD. 10 The presence of a genetic defect in UMOD in MCKD2, FJHN, and GCKD (discussed next) showed that these 3 conditions are allelic.…”

Section: Heterogeneity Of Clinical Conditions Associated With Uromodumentioning

confidence: 99%

“…Overall, 8 families with MCKD2 and 24 families with FJHN have been described. [6][7][8][9][10][11][12][13] A common motif to all reports is that so many overlapping symptoms between MCKD2 and FJHN are present that separation between these 2 entities seems artful and probably clinically useless. For this reason, in the following sections devoted to the clinical description of UMOD-related diseases and genotype-phenotype correlations, MCKD2 and FJHN are discussed together.…”

Section: Heterogeneity Of Clinical Conditions Associated With Uromodumentioning

confidence: 99%

“…1 As discussed previously, severe impairment of urinaryconcentrating capability is a major and almost constant clinical symptom in all patients with MCKD/FJHN, whereas hyperuricemia is not constant and often is associated with renal cysts. [6][7][8][9][10][11][12][13] It is of note that some pathological and biochemical features, such as tubulointerstitial fibrosis, formation of medullary and cortical cysts (in patients with MCKD2 and GCKD, respectively), and hyperuricemia remain difficult to explain on the basis of the protein putative function(s).…”

Section: Pathological Examination and Mechanisms Of Gross Symptomsmentioning

confidence: 99%

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Uromodulin storage diseases: Clinical aspects and mechanisms

Scolari

Caridi

Rampoldi

et al. 2004

American Journal of Kidney Diseases

124

100

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• 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.

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supporting

confidence: 75%

Section: Heterogeneity Of Clinical Conditions Associated With Uromodumentioning

confidence: 99%

Section: Heterogeneity Of Clinical Conditions Associated With Uromodumentioning

confidence: 99%

Section: Pathological Examination and Mechanisms Of Gross Symptomsmentioning

confidence: 99%

See 2 more Smart Citations

Uromodulin storage diseases: Clinical aspects and mechanisms

Scolari

Caridi

Rampoldi

et al. 2004

American Journal of Kidney Diseases

124

100

View full text Add to dashboard Cite

show abstract

“…To date, over 50 UMOD mutations have been described, of which >90 % are missense mutations and >60 % affect the cysteine residues. The majority of these mutations are clustered in exons 4 and 5 and located in the N-terminal half of the protein [21][22][23][24][25]. The mutations cause significantly delayed maturation and trafficking of the mutant uromodulin, which in turn results in its retention in the ER, reduced expression at the plasma membrane, and decreased secretion into the tubular lumen [24,[26][27][28].…”

Section: Pathophysiologymentioning

confidence: 99%