Mechanism of Release of Urinary Tamm-Horsfall Glycoprotein from the Kidney GPI-Anchored Counterpart

Cavallone, D.; Malagolini, Nadia; Serafini‐Cessi, Franca

doi:10.1006/bbrc.2000.4090

Cited by 77 publications

(53 citation statements)

References 32 publications

(25 reference statements)

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“…Taken together, our data suggest that only wild-type uromodulin is excreted in the urine of patients with UMOD mutations, whereas mutated uromodulin accumulates within tubular cells. The accumulation could result from (1) a gain of function leading to an increased production of uromodulin, (2) an abnormal targeting (by disturbance of the GPI anchor signal) (45), or (3) an impaired clearance of the protein from the epithelial cell surface through a gain of resistance to proteolytic cleavage (46). Our findings support previous observations (47,48) indicating that hyperuricemia is the primary clinical finding in FJHN.…”

Section: Discussionsupporting

confidence: 89%

A Cluster of Mutations in the UMOD Gene Causes Familial Juvenile Hyperuricemic Nephropathy with Abnormal Expression of Uromodulin

Dahan¹,

Devuyst²,

Smaers³

et al. 2003

Journal of the American Society of Nephrology

201

170

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Abstract. Familial juvenile hyperuricemic nephropathy (FJHN [MIM 162000]) is an autosomal-dominant disorder characterized by abnormal tubular handling of urate and late development of chronic interstitial nephritis leading to progressive renal failure. A locus for FJHN was previously identified on chromosome 16p12 close to the MCKD2 locus, which is responsible for a variety of autosomal-dominant medullary cystic kidney disease (MCKD2). UMOD, the gene encoding the Tamm-Horsfall/uromodulin protein, maps within the FJHN/MCKD2 critical region. Mutations in UMOD were recently reported in nine families with FJHN/ MCKD2 disease. A mutation in UMOD has been identified in 11 FJHN families (10 missense and one in-frame deletion)-10 of which are novel-clustering in the highly conserved exon 4. The consequences of UMOD mutations on uromodulin expression were investigated in urine samples and renal biopsies from nine patients in four families. There was a markedly increased expression of uromodulin in a cluster of tubule profiles, suggesting an accumulation of the protein in tubular cells. Consistent with this observation, urinary excretion of wild-type uromodulin was significantly decreased. The latter findings were not observed in patients with FJHN without UMOD mutations. In conclusion, this study points to a mutation clustering in exon 4 of UMOD as a major genetic defect in FJHN. Mutations in UMOD may critically affect the function of uromodulin, resulting in abnormal accumulation within tubular cells and reduced urinary excretion.Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal-dominant disorder characterized by hyperuricemia and decreased urinary excretion of urate, followed by the development of chronic interstitial nephritis most often leading to progressive renal failure (1,2). The link between early hyperuricemia and subsequent progression of renal disease remains unclear.Urate is the end product of purine metabolism in humans, who have lost the expression of the uricase gene during evolution (3). Urate is freely filtered by the glomerulus and essentially reabsorbed, because only 10% of the filtered load is present in the final urine (4). The transport mechanisms of urate are localized in the proximal tubule (PT), whereas no experimental evidence supports urate permeability in the more distal segments of the nephron (5). URAT1, the long-hypothesized apical urate-anion exchanger involved in the reabsorption of urate by PT cells, was recently identified (6). Inactivating mutations of URAT1 located on 11q13 are responsible

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Section: Discussionsupporting

confidence: 89%

A Cluster of Mutations in the UMOD Gene Causes Familial Juvenile Hyperuricemic Nephropathy with Abnormal Expression of Uromodulin

Dahan¹,

Devuyst²,

Smaers³

et al. 2003

Journal of the American Society of Nephrology

201

170

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“…THP exposed at the luminal face of TAL is released in urine by proteolytic cleavage of the large ectodomain of GPIanchored domain (21). THP is the most common protein in healthy urine.…”

Section: Discussionmentioning

confidence: 99%

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

Choi

Ryu²,

Choi³

et al. 2005

Journal of the American Society of Nephrology

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“…Normally the synthesized protein is glycosylated, glypiated, secreted and glycosylphosphatidylinositol-anchored in the apical membrane of the polarized renal tubular epithelial cells (Kreft et al 2002;Rindler et al 1990;Serafini-Cessi et al 1993), from where it is continuously released by a specific but not yet identified protease (Cavallone et al 2001;Fukuoka and Kobayashi 2001). UMOD is excreted in the urine at the rate of 50-100 mg/day, which makes it one of the most abundant urinary proteins (Kumar and Muchmore 1990).…”

mentioning

confidence: 99%

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

Vyleťal

Hůlková

Živná

et al. 2008

J of Inher Metab Disea

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Summary Uromodulin (UMOD) malfunction has been found in a range of autosomal dominant tubulointerstitial nephropathies associated with hyperuricaemia, gouty arthritis, medullary cysts and renal failure—labelled as familial juvenile hyperuricaemic nephropathy, medullary cystic disease type 2 and glomerulocystic kidney disease. To gain knowledge of the spectrum of UMOD changes in various genetic diseases with renal involvement we examined urinary UMOD excretion and found significant quantitative and qualitative changes in 15 male patients at various clinical stages of Fabry disease. In untreated patients, the changes ranged from normal to a marked decrease, or even absence of urinary UMOD. This was accompanied frequently by the presence of aberrantly processed UMOD lacking the C‐terminal part following the K432 residue. The abnormal patterns normalized in all patients on enzyme replacement therapy and in some patients on substrate reduction therapy. Immunohistochemical analysis of the affected kidney revealed abnormal UMOD localization in the thick ascending limb of Henle's loop and the distal convoluted tubule, with UMOD expression inversely proportional to the degree of storage. Our observations warrant evaluation of tubular functions in Fabry disease and suggest UMOD as a potential biochemical marker of therapeutic response of the kidney to therapy. Extended comparative studies of UMOD expression in kidney specimens obtained during individual types of therapies are therefore of great interest.

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Mechanism of Release of Urinary Tamm-Horsfall Glycoprotein from the Kidney GPI-Anchored Counterpart

Cited by 77 publications

References 32 publications

A Cluster of Mutations in the UMOD Gene Causes Familial Juvenile Hyperuricemic Nephropathy with Abnormal Expression of Uromodulin

A Cluster of Mutations in the UMOD Gene Causes Familial Juvenile Hyperuricemic Nephropathy with Abnormal Expression of Uromodulin

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

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

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