Uromodulin (UMOD), also known as Tamm–Horsfall protein (THP), is a zona pellucida-like domain-containing glycoprotein that in humans is encoded by the UMOD gene.[5][6] Uromodulin is the most abundant protein excreted in ordinary urine.[7]
Quick Facts UMOD, Available structures ...
Close
The human UMOD gene is located on chromosome 16. While several transcript variants may exist for this gene, the full-length natures of only two have been described to date. These two represent the major variants of this gene and encode the same isoform.[6]
THP is a GPI-anchored glycoprotein. It is not derived from blood plasma but is produced by the thick ascending limb of the loop of Henle of the mammalian kidney. While the monomeric molecule has a MW of approximately 85 kDa, it is physiologically present in urine in large aggregates of up to several million Da.[7] When this protein is concentrated at low pH, it forms a gel. Uromodulin represents the most abundant protein in normal human urine (results based on MSMS determinations).[8] It is the matrix of urinary casts derived from the secretion of renal tubular cells.
Uromodulin consists of an EGF domain (EGF I); two calcium-binding EGF domains (EGF II, III); a cysteine-rich decoy module consisting of a β-hairpin and a D10C domain (previously referred to as D8C); a fourth EGF domain; and a C-terminal bipartite Zona pellucida-like (ZP) module consisting of ZP-N and ZP-C domains separated by an interdomain linker.[9][10] The ZP domain polymerizes into filaments,[11] with protruding arms that correspond to the EGF I-III domains and the decoy module.[10][12][13][14]
Uromodulin excretion in urine follows proteolytic cleavage of the ectodomain of its glycophosphatidylinositol-anchored counterpart that is situated on the luminal cell surface of the loop of Henle. Uromodulin may act as a constitutive inhibitor of calcium crystallization in renal fluids. The excretion of uromodulin in urine may provide defense against urinary tract infections caused by uropathogenic bacteria.[6]
The function of THP is not well understood. Studies using THP deficient mice revealed that THP may have a role in regulatory physiology and actually participates in transporter function.[15] A role in bacterial binding and sequestration is suggested by studies showing that Escherichia coli which express MS (mannose-sensitive) pili or fimbriae (also fimbria, from the Latin word for "fringe") can be trapped by Tamm–Horsfall protein via its mannose-containing side chains.[7] THP may also be important in protection from kidney injury by down-regulating inflammation.[16]
Uropontin, nephrocalcin and uromodulin (this protein) are the three known urinary glycoproteins that affect the formation of calcium-containing kidney stones or calculus. Tamm–Horsfall protein is part of the matrix in renal calculi but a role in kidney stone formation remains debatable. However, decreased levels of Tamm–Horsfall in urine have been found to be a good indicator of kidney stones.[7]
Defects in this gene are associated with the autosomal dominant renal disorders medullary cystic kidney disease-2 (MCKD2) and autosomal dominant tubulointerstitial kidney disease (ADTKD) (previously familial juvenile hyperuricemic nephropathy (FJHN)). These disorders are characterized by juvenile onset of hyperuricemia, gout, and progressive kidney failure.[6]
Antibodies to Tamm–Horsfall protein have been seen in various forms of nephritis (e.g., Balkan nephropathy), however, it remains unclear whether there is any pathophysiologic relevance to these findings.[17]
Another disease associated with mutations in this gene is Uromodulin-associated Kidney Disease (UKD), a rare autosomal dominant progressive failure of the kidneys.
In multiple myeloma, there is often protein cast in the distal convoluted tubule and collecting duct of the kidneys, mainly consisting of immunoglobulin light chain known as Bence Jones protein, but often also containing Tamm–Horsfall protein.[18][19] This is known as myeloma cast nephropathy.
The glycoprotein was first purified in 1950 by Igor Tamm and Frank Horsfall from the urine of healthy individuals.[20] It was later detected in the urine of all mammals studied.
Jeanpierre C, Whitmore SA, Austruy E, Cohen-Salmon M, Callen DF, Junien C (March 1993). "Chromosomal assignment of the uromodulin gene (UMOD) to 16p13.11". Cytogenetics and Cell Genetics. 62 (4): 185–7. doi:10.1159/000133470. PMID 8382593. Nagaraj N, Mann M (February 2011). "Quantitative analysis of the intra- and inter-individual variability of the normal urinary proteome". Journal of Proteome Research. 10 (2): 637–45. doi:10.1021/pr100835s. PMID 21126025. Stsiapanava A, Xu C, Nishio S, Han L, Yamakawa N, Carroni M, Tunyasuvunakool K, Jumper J, de Sanctis D, Wu B, Jovine L (2022). "Structure of the decoy module of human glycoprotein 2 and uromodulin and its interaction with bacterial adhesin FimH". Nat. Struct. Mol. Biol. 29 (3): 190–193. doi:10.1038/s41594-022-00729-3. PMC 8930769. PMID 35273390. PDB: 7PFP, 7Q3N Jovine L, Qi H, Williams Z, Litscher E, de Sanctis D, Wassarman PM (2002). "The ZP domain is a conserved module for polymerization of extracellular proteins". Nat. Cell Biol. 4 (6): 457–461. doi:10.1038/ncb802. PMID 12021773. S2CID 11575790. Stsiapanava A, Xu C, Brunati M, Zamora-Caballero S, Schaeffer C, Bokhove M, Han L, Hebert H, Carroni M, Yasumasu S, Rampoldi L, Wu B, Jovine L (2020). "Cryo-EM structure of native human uromodulin, a zona pellucida module polymer". EMBO J. 39 (24): e106807. doi:10.15252/embj.2020106807. PMC 7737619. PMID 33196145. bioRxiv 10.1101/2020.05.28.119206 PDB: 6TQK, 6TQL Weiss GL, Stanisich JJ, Sauer MM, Lin CW, Eras J, Zyla DS, Trück J, Devuyst O, Aebi M, Pilhofer M, Glockshuber R (2020). "Architecture and function of human uromodulin filaments in urinary tract infections". Science. 369 (6506). New York, N.Y.: 1005–1010. doi:10.1126/science.aaz9866. hdl:20.500.11850/438598. PMID 32616672. S2CID 220328267. Stanisich JJ, Zyla DS, Afanasyev P, Xu J, Kipp A, Olinger E, Devuyst O, Pilhofer M, Boehringer D, Glockshuber R (2020). "The cryo-EM structure of the human uromodulin filament core reveals a unique assembly mechanism". eLife. 9: e60265. doi:10.7554/eLife.60265. PMC 7486124. PMID 32815518. PDB: 6ZS5, 6ZYA Bachmann S, Mutig K, Bates J, Welker P, Geist B, Gross V, et al. (March 2005). "Renal effects of Tamm-Horsfall protein (uromodulin) deficiency in mice". American Journal of Physiology. Renal Physiology. 288 (3): F559-67. doi:10.1152/ajprenal.00143.2004. PMID 15522986. S2CID 33703271. Vizjak A, Trnacević S, Ferluga D, Halilbasić A (November 1991). "Renal function, protein excretion, and pathology of Balkan endemic nephropathy. IV. Immunohistology". Kidney International. 34: S68-74. PMID 1762338. Aster JC (2007). "The Hematopoietic and Lymphoid Systems". In Kumar V, Abbas AK, Fauso N, Mitchell R (eds.). Robbins Basic Patholog (8th ed.). Philadelphia, PA: Saunders/Elsevier. p. 455. ISBN 978-1-4160-2973-1.
- Scolari F, Viola BF, Ghiggeri GM, Caridi G, Amoroso A, Rampoldi L, Casari G (2003). "Towards the identification of (a) gene(s) for autosomal dominant medullary cystic kidney disease". Journal of Nephrology. 16 (3): 321–8. PMID 12832729.
- Rindler MJ, Naik SS, Li N, Hoops TC, Peraldi MN (December 1990). "Uromodulin (Tamm-Horsfall glycoprotein/uromucoid) is a phosphatidylinositol-linked membrane protein". The Journal of Biological Chemistry. 265 (34): 20784–9. doi:10.1016/S0021-9258(17)45284-7. PMID 2249987.
- Muchmore AV, Decker JM (August 1985). "Uromodulin: a unique 85-kilodalton immunosuppressive glycoprotein isolated from urine of pregnant women". Science. 229 (4712): 479–81. Bibcode:1985Sci...229..479M. doi:10.1126/science.2409603. PMID 2409603.
- Pennica D, Kohr WJ, Kuang WJ, Glaister D, Aggarwal BB, Chen EY, Goeddel DV (April 1987). "Identification of human uromodulin as the Tamm-Horsfall urinary glycoprotein". Science. 236 (4797): 83–8. Bibcode:1987Sci...236...83P. doi:10.1126/science.3453112. PMID 3453112.
- Hession C, Decker JM, Sherblom AP, Kumar S, Yue CC, Mattaliano RJ, et al. (September 1987). "Uromodulin (Tamm-Horsfall glycoprotein): a renal ligand for lymphokines". Science. 237 (4821): 1479–84. Bibcode:1987Sci...237.1479H. doi:10.1126/science.3498215. PMID 3498215.
- Prasadan K, Bates J, Badgett A, Dell M, Sukhatme V, Yu H, Kumar S (February 1995). "Nucleotide sequence and peptide motifs of mouse uromodulin (Tamm-Horsfall protein)--the most abundant protein in mammalian urine". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1260 (3): 328–32. doi:10.1016/0167-4781(94)00240-4. PMID 7873609.
- Huang ZQ, Kirk KA, Connelly KG, Sanders PW (December 1993). "Bence Jones proteins bind to a common peptide segment of Tamm-Horsfall glycoprotein to promote heterotypic aggregation". The Journal of Clinical Investigation. 92 (6): 2975–83. doi:10.1172/JCI116920. PMC 288501. PMID 8254051.
- Rhodes DC, Hinsman EJ, Rhodes JA (November 1993). "Tamm-Horsfall glycoprotein binds IgG with high affinity". Kidney International. 44 (5): 1014–21. doi:10.1038/ki.1993.343. PMID 8264130.
- Fukushima K, Watanabe H, Takeo K, Nomura M, Asahi T, Yamashita K (July 1993). "N-linked sugar chain structure of recombinant human lymphotoxin produced by CHO cells: the functional role of carbohydrate as to its lectin-like character and clearance velocity". Archives of Biochemistry and Biophysics. 304 (1): 144–53. doi:10.1006/abbi.1993.1332. PMID 8323280.
- Thomas DB, Davies M, Peters JR, Williams JD (August 1993). "Tamm Horsfall protein binds to a single class of carbohydrate specific receptors on human neutrophils". Kidney International. 44 (2): 423–9. doi:10.1038/ki.1993.260. PMID 8397318.
- Badgett A, Kumar S (1999). "Phylogeny of Tamm-Horsfall protein". Urologia Internationalis. 61 (2): 72–5. doi:10.1159/000030292. PMID 9873244. S2CID 23027802.
- van Rooijen JJ, Voskamp AF, Kamerling JP, Vliegenthart JF (January 1999). "Glycosylation sites and site-specific glycosylation in human Tamm-Horsfall glycoprotein". Glycobiology. 9 (1): 21–30. doi:10.1093/glycob/9.1.21. PMID 9884403.
- Scolari F, Puzzer D, Amoroso A, Caridi G, Ghiggeri GM, Maiorca R, et al. (June 1999). "Identification of a new locus for medullary cystic disease, on chromosome 16p12". American Journal of Human Genetics. 64 (6): 1655–60. doi:10.1086/302414. PMC 1377908. PMID 10330352.
- Kamatani N, Moritani M, Yamanaka H, Takeuchi F, Hosoya T, Itakura M (April 2000). "Localization of a gene for familial juvenile hyperuricemic nephropathy causing underexcretion-type gout to 16p12 by genome-wide linkage analysis of a large family" (PDF). Arthritis and Rheumatism. 43 (4): 925–9. CiteSeerX 10.1.1.542.8350. doi:10.1002/1529-0131(200004)43:4<925::AID-ANR26>3.0.CO;2-B. PMID 10765940.
- Pirulli D, Puzzer D, De Fusco M, Crovella S, Amoroso A, Scolari F, et al. (2002). "Molecular analysis of uromodulin and SAH genes, positional candidates for autosomal dominant medullary cystic kidney disease linked to 16p12". Journal of Nephrology. 14 (5): 392–6. PMID 11730273.
- Menozzi FD, Debrie AS, Tissier JP, Locht C, Pethe K, Raze D (April 2002). "Interaction of human Tamm-Horsfall glycoprotein with Bordetella pertussis toxin". Microbiology. 148 (Pt 4): 1193–1201. doi:10.1099/00221287-148-4-1193. PMID 11932463.
- Zbikowska HM, Soukhareva N, Behnam R, Lubon H, Hammond D, Soukharev S (July 2002). "Uromodulin promoter directs high-level expression of biologically active human alpha1-antitrypsin into mouse urine". The Biochemical Journal. 365 (Pt 1): 7–11. doi:10.1042/BJ20020643. PMC 1222653. PMID 11982485.
- Hart TC, Gorry MC, Hart PS, Woodard AS, Shihabi Z, Sandhu J, et al. (December 2002). "Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy". Journal of Medical Genetics. 39 (12): 882–92. doi:10.1136/jmg.39.12.882. PMC 1757206. PMID 12471200.
