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UMOD  -  uromodulin

Homo sapiens

Synonyms: ADMCKD2, FJHN, HNFJ, HNFJ1, MCKD2, ...
 
 
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Disease relevance of UMOD

  • Such effects may also play an important role in the pathogenesis of the progressive renal failure observed in patients with UMOD gene mutations [1].
  • BACKGROUND: Mutations in the uromodulin (UMOD) gene that encodes Tamm-Horsfall protein (THP) cause an autosomal-dominant form of chronic renal failure [1].
  • Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy [2].
  • METHODS: We characterized the intron-exon boundary sequences by screening phage and BAC DNA genomic clones for the development of new molecular tools functional to the mutation analysis of UMOD and SAH genes [3].
  • We postulate that mutation of UMOD disrupts the tertiary structure of UMOD and is responsible for the clinical changes of interstitial renal disease, polyuria, and hyperuricaemia found in MCKD2 and FJHN [2].
 

Psychiatry related information on UMOD

  • CONCLUSIONS: Both in C and SF, urinary THP excretion is related to body size, renal function and urinary citrate excretion, whereas dietary habits apparently do not affect THP excretion [4].
  • CONCLUSIONS: These experiments suggest that THP has an important role in bladder mucosal defense mechanisms, protecting the bladder surface from injury [5].
 

High impact information on UMOD

  • Thus, uromodulin (Tamm-Horsfall glycoprotein) may function as a unique renal regulatory glycoprotein that specifically binds to and regulates the circulating activity of a number of potent cytokines, including IL-1 and TNF [6].
  • Uromodulin (Tamm-Horsfall glycoprotein): a renal ligand for lymphokines [6].
  • Nucleic acid sequencing of clones for uromodulin isolated from a complementary DNA bank from human kidney predicts a protein 639 amino acids in length, including a 24--amino acid leader sequence and a cysteine-rich mature protein with eight potential glycosylation sites [6].
  • The amino acid sequence encoded by one of the exons of the uromodulin gene has homology to the low-density-lipoprotein receptor and the epidermal growth factor precursor [7].
  • Here we show that THP (allopregnanolone), a steroid that is released as a result of stress, increases anxiety in pubertal female mice, in contrast to its anxiety-reducing effect in adults [8].
 

Chemical compound and disease context of UMOD

  • 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 [9].
  • Tamm-Horsfall glycoprotein (THP), the most abundant protein in mammalian urine, has been implicated in defending the urinary tract against infections by type 1-fimbriated Escherichia coli [10].
  • Recent experimental evidence indicates that the defensive capability of THP relies on its single high mannose chain, which binds to E. coli FimH lectin and competes with mannosylated uroplakin receptors on the bladder surface [10].
  • Uromodulin does not inhibit the cytotoxic activity of rTNF as monitored by lysis of tumor cell targets but effectively protects mice from lethal challenge with lipopolysaccharide, an event that may involve lymphokine toxicity [11].
  • Colchicine and sodium 4-phenylbutyrate reverse these processes and could potentially be beneficial in ameliorating the progressive renal damage in uromodulin-associated kidney diseases [12].
 

Biological context of UMOD

  • In three different families, three novel heterozygous mutations in the UMOD gene were found and segregated with the phenotype in affected individuals [13].
  • In the kindreds showing linkage to the MCKD2 locus on chromosome 16p12, mutational analysis of the UMOD gene was performed by exon polymerase chain reaction (PCR) and direct sequencing [13].
  • All individuals with UMOD mutations had low THP excretion, irrespective of gender, glomerular filtration rate (GFR), or age [1].
  • Revised multipoint linkage analysis showed that the UMOD gene was located in the interval showing logarithm of odds (LOD) score above 6 [14].
  • CONCLUSION: The study shows that individuals with two UMOD mutations are viable, but they do have more severe disease on average than heterozygotes [15].
 

Anatomical context of UMOD

 

Associations of UMOD with chemical compounds

  • We noted that affected individuals showed, in addition to the characteristic urate hypoexcretion, significant reductions in urinary excretion of calcium and UMOD [20].
  • UMOD is a GPI anchored glycoprotein and the most abundant protein in normal urine [2].
  • In addition, unlike hTHP whose polyantennary glycans are exclusively capped by sialic acid and sulfate groups, those of pTHP are also terminated by Galalpha1,3Gal epitope [10].
  • This suggests that the shorter high mannose chain (Man5GlcNAc2) is a much better binder for FimH than the longer chains (Man6-7GlcNAc2) and that pTHP is a more potent urinary defense factor than hTHP [10].
  • In transfected cell extracts, THP also remained primarily in the detergent phase in a Triton X-114 partitioning assay, indicating that it has a hydrophobic character, in contrast to its behavior after isolation from human urine [18].
 

Physical interactions of UMOD

  • The disease complex medullary cystic disease/familial juvenile hyperuricemic nephropathy (MCKD/FJHN) is characterized by alteration of urinary concentrating ability, frequent hyperuricemia, tubulo-interstitial fibrosis, cysts at the cortico-medullary junction and renal failure [17].
  • On the other hand, we found that the recently described ability of the wild type betaglycan to bind inhibin A is a property of the core protein that resides in the uromodulin-related region [21].
  • Evidence that recombinant IL 1 alpha exhibits lectin-like specificity and binds to homogeneous uromodulin via N-linked oligosaccharides [22].
  • Uromodulin bound with high affinity to human tumour necrosis factor (TNF) coated on microtitre plates [23].
 

Regulatory relationships of UMOD

 

Other interactions of UMOD

 

Analytical, diagnostic and therapeutic context of UMOD

References

  1. Mutations in the uromodulin gene decrease urinary excretion of Tamm-Horsfall protein. Bleyer, A.J., Hart, T.C., Shihabi, Z., Robins, V., Hoyer, J.R. Kidney Int. (2004) [Pubmed]
  2. Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. Hart, T.C., Gorry, M.C., Hart, P.S., Woodard, A.S., Shihabi, Z., Sandhu, J., Shirts, B., Xu, L., Zhu, H., Barmada, M.M., Bleyer, A.J. J. Med. Genet. (2002) [Pubmed]
  3. Molecular analysis of uromodulin and SAH genes, positional candidates for autosomal dominant medullary cystic kidney disease linked to 16p12. Pirulli, D., Puzzer, D., De Fusco, M., Crovella, S., Amoroso, A., Scolari, F., Viola, B.F., Maiorca, R., Caridi, G., Savoldi, S., Ghiggeri, G., Casari, G. J. Nephrol. (2001) [Pubmed]
  4. Determinants of urinary excretion of Tamm-Horsfall protein in non-selected kidney stone formers and healthy subjects. Glauser, A., Hochreiter, W., Jaeger, P., Hess, B. Nephrol. Dial. Transplant. (2000) [Pubmed]
  5. Urothelial cytoprotective activity of Tamm-Horsfall protein isolated from the urine of healthy subjects and patients with interstitial cystitis. Akiyama, A., Stein, P.C., Houshiar, A., Parsons, C.L. International journal of urology : official journal of the Japanese Urological Association. (2000) [Pubmed]
  6. Uromodulin (Tamm-Horsfall glycoprotein): a renal ligand for lymphokines. Hession, C., Decker, J.M., Sherblom, A.P., Kumar, S., Yue, C.C., Mattaliano, R.J., Tizard, R., Kawashima, E., Schmeissner, U., Heletky, S. Science (1987) [Pubmed]
  7. Identification of human uromodulin as the Tamm-Horsfall urinary glycoprotein. Pennica, D., Kohr, W.J., Kuang, W.J., Glaister, D., Aggarwal, B.B., Chen, E.Y., Goeddel, D.V. Science (1987) [Pubmed]
  8. Reversal of neurosteroid effects at alpha4beta2delta GABA(A) receptors triggers anxiety at puberty. Shen, H., Gong, Q.H., Aoki, C., Yuan, M., Ruderman, Y., Dattilo, M., Williams, K., Smith, S.S. Nat. Neurosci. (2007) [Pubmed]
  9. A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin. Dahan, K., Devuyst, O., Smaers, M., Vertommen, D., Loute, G., Poux, J.M., Viron, B., Jacquot, C., Gagnadoux, M.F., Chauveau, D., Büchler, M., Cochat, P., Cosyns, J.P., Mougenot, B., Rider, M.H., Antignac, C., Verellen-Dumoulin, C., Pirson, Y. J. Am. Soc. Nephrol. (2003) [Pubmed]
  10. Variation of high mannose chains of Tamm-Horsfall glycoprotein confers differential binding to type 1-fimbriated Escherichia coli. Cavallone, D., Malagolini, N., Monti, A., Wu, X.R., Serafini-Cessi, F. J. Biol. Chem. (2004) [Pubmed]
  11. The lectin-like interaction between recombinant tumor necrosis factor and uromodulin. Sherblom, A.P., Decker, J.M., Muchmore, A.V. J. Biol. Chem. (1988) [Pubmed]
  12. Mutant tamm-horsfall glycoprotein accumulation in endoplasmic reticulum induces apoptosis reversed by colchicine and sodium 4-phenylbutyrate. Choi, S.W., Ryu, O.H., Choi, S.J., Song, I.S., Bleyer, A.J., Hart, T.C. J. Am. Soc. Nephrol. (2005) [Pubmed]
  13. Mutations of the Uromodulin gene in MCKD type 2 patients cluster in exon 4, which encodes three EGF-like domains. Wolf, M.T., Mucha, B.E., Attanasio, M., Zalewski, I., Karle, S.M., Neumann, H.P., Rahman, N., Bader, B., Baldamus, C.A., Otto, E., Witzgall, R., Fuchshuber, A., Hildebrandt, F. Kidney Int. (2003) [Pubmed]
  14. Familial juvenile hyperuricemic nephropathy: detection of mutations in the uromodulin gene in five Japanese families. Kudo, E., Kamatani, N., Tezuka, O., Taniguchi, A., Yamanaka, H., Yabe, S., Osabe, D., Shinohara, S., Nomura, K., Segawa, M., Miyamoto, T., Moritani, M., Kunika, K., Itakura, M. Kidney Int. (2004) [Pubmed]
  15. Homozygosity for uromodulin disorders: FJHN and MCKD-type 2. Rezende-Lima, W., Parreira, K.S., García-González, M., Riveira, E., Banet, J.F., Lens, X.M. Kidney Int. (2004) [Pubmed]
  16. Chromosomal assignment of the uromodulin gene (UMOD) to 16p13.11. Jeanpierre, C., Whitmore, S.A., Austruy, E., Cohen-Salmon, M., Callen, D.F., Junien, C. Cytogenet. Cell Genet. (1993) [Pubmed]
  17. Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export dynamics. Rampoldi, L., Caridi, G., Santon, D., Boaretto, F., Bernascone, I., Lamorte, G., Tardanico, R., Dagnino, M., Colussi, G., Scolari, F., Ghiggeri, G.M., Amoroso, A., Casari, G. Hum. Mol. Genet. (2003) [Pubmed]
  18. Uromodulin (Tamm-Horsfall glycoprotein/uromucoid) is a phosphatidylinositol-linked membrane protein. Rindler, M.J., Naik, S.S., Li, N., Hoops, T.C., Peraldi, M.N. J. Biol. Chem. (1990) [Pubmed]
  19. Tamm Horsfall protein binds to a single class of carbohydrate specific receptors on human neutrophils. Thomas, D.B., Davies, M., Peters, J.R., Williams, J.D. Kidney Int. (1993) [Pubmed]
  20. Mapping of a new candidate locus for uromodulin-associated kidney disease (UAKD) to chromosome 1q41. Hodanová, K., Majewski, J., Kublová, M., Vyletal, P., Kalbácová, M., Stibůrková, B., Hůlková, H., Chagnon, Y.C., Lanouette, C.M., Marinaki, A., Fryns, J.P., Venkat-Raman, G., Kmoch, S. Kidney Int. (2005) [Pubmed]
  21. Ligand binding and functional properties of betaglycan, a co-receptor of the transforming growth factor-beta superfamily. Specialized binding regions for transforming growth factor-beta and inhibin A. Esparza-Lopez, J., Montiel, J.L., Vilchis-Landeros, M.M., Okadome, T., Miyazono, K., López-Casillas, F. J. Biol. Chem. (2001) [Pubmed]
  22. Evidence that recombinant IL 1 alpha exhibits lectin-like specificity and binds to homogeneous uromodulin via N-linked oligosaccharides. Muchmore, A.V., Decker, J.M. J. Immunol. (1987) [Pubmed]
  23. Native cytokines do not bind to uromodulin (Tamm-Horsfall glycoprotein). Moonen, P., Gaffner, R., Wingfield, P. FEBS Lett. (1988) [Pubmed]
  24. Uromodulin, an immunosuppressive protein derived from pregnancy urine, is an inhibitor of interleukin 1. Brown, K.M., Muchmore, A.V., Rosenstreich, D.L. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  25. Identification and characterization of D8C, a novel domain present in liver-specific LZP, uromodulin and glycoprotein 2, mutated in familial juvenile hyperuricaemic nephropathy. Yang, H., Wu, C., Zhao, S., Guo, J. FEBS Lett. (2004) [Pubmed]
  26. A novel heterozygous missense mutation in the UMOD gene responsible for Familial Juvenile Hyperuricemic Nephropathy. Calado, J., Gaspar, A., Clemente, C., Rueff, J. BMC Med. Genet. (2005) [Pubmed]
  27. A novel pattern of mutation in uromodulin disorders: autosomal dominant medullary cystic kidney disease type 2, familial juvenile hyperuricemic nephropathy, and autosomal dominant glomerulocystic kidney disease. Lens, X.M., Banet, J.F., Outeda, P., Barrio-Lucía, V. Am. J. Kidney Dis. (2005) [Pubmed]
  28. Tamm-Horsfall glycoprotein binds IgG with high affinity. Rhodes, D.C., Hinsman, E.J., Rhodes, J.A. Kidney Int. (1993) [Pubmed]
 
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