Uromodulin Explained

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.^{[1] [2]} Uromodulin is the most abundant protein excreted in ordinary urine.^[3]

Gene

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.^[2]

Protein

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.^[3] 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).^[4] It is the matrix of urinary casts derived from the secretion of renal tubular cells.

Structure

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.^{[5] [6]} The ZP domain polymerizes into filaments,^[7] with protruding arms that correspond to the EGF I-III domains and the decoy module.^{[6] [8] [9] [10]}

Function

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.^[2]

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.^[11] 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. THP may also be important in protection from kidney injury by down-regulating inflammation.^[12]

Clinical significance

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.

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.^[2]

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.^[13]

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.^{[14] [15]} This is known as myeloma cast nephropathy.

History

The glycoprotein was first purified in 1950 by Igor Tamm and Frank Horsfall from the urine of healthy individuals.^[16] It was later detected in the urine of all mammals studied.

Further reading

• Scolari F, Viola BF, Ghiggeri GM, Caridi G, Amoroso A, Rampoldi L, Casari G . Towards the identification of (a) gene(s) for autosomal dominant medullary cystic kidney disease . Journal of Nephrology . 16 . 3 . 321–8 . 2003 . 12832729 .
• Rindler MJ, Naik SS, Li N, Hoops TC, Peraldi MN . Uromodulin (Tamm-Horsfall glycoprotein/uromucoid) is a phosphatidylinositol-linked membrane protein . The Journal of Biological Chemistry . 265 . 34 . 20784–9 . December 1990 . 10.1016/S0021-9258(17)45284-7 . 2249987 . free .
• Muchmore AV, Decker JM . Uromodulin: a unique 85-kilodalton immunosuppressive glycoprotein isolated from urine of pregnant women . Science . 229 . 4712 . 479–81 . August 1985 . 2409603 . 10.1126/science.2409603 . 1985Sci...229..479M .
• Pennica D, Kohr WJ, Kuang WJ, Glaister D, Aggarwal BB, Chen EY, Goeddel DV . Identification of human uromodulin as the Tamm-Horsfall urinary glycoprotein . Science . 236 . 4797 . 83–8 . April 1987 . 3453112 . 10.1126/science.3453112 . 1987Sci...236...83P .
• Hession C, Decker JM, Sherblom AP, Kumar S, Yue CC, Mattaliano RJ, Tizard R, Kawashima E, Schmeissner U, Heletky S . 6 . Uromodulin (Tamm-Horsfall glycoprotein): a renal ligand for lymphokines . Science . 237 . 4821 . 1479–84 . September 1987 . 3498215 . 10.1126/science.3498215 . 1987Sci...237.1479H .
• Prasadan K, Bates J, Badgett A, Dell M, Sukhatme V, Yu H, Kumar S . 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 . February 1995 . 7873609 . 10.1016/0167-4781(94)00240-4 .
• Huang ZQ, Kirk KA, Connelly KG, Sanders PW . 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 . December 1993 . 8254051 . 288501 . 10.1172/JCI116920 .
• Rhodes DC, Hinsman EJ, Rhodes JA . Tamm-Horsfall glycoprotein binds IgG with high affinity . Kidney International . 44 . 5 . 1014–21 . November 1993 . 8264130 . 10.1038/ki.1993.343 . free .
• Fukushima K, Watanabe H, Takeo K, Nomura M, Asahi T, Yamashita K . 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 . July 1993 . 8323280 . 10.1006/abbi.1993.1332 .
• Thomas DB, Davies M, Peters JR, Williams JD . Tamm Horsfall protein binds to a single class of carbohydrate specific receptors on human neutrophils . Kidney International . 44 . 2 . 423–9 . August 1993 . 8397318 . 10.1038/ki.1993.260 . free .
• Badgett A, Kumar S . Phylogeny of Tamm-Horsfall protein . Urologia Internationalis . 61 . 2 . 72–5 . 1999 . 9873244 . 10.1159/000030292 . 23027802 .
• van Rooijen JJ, Voskamp AF, Kamerling JP, Vliegenthart JF . Glycosylation sites and site-specific glycosylation in human Tamm-Horsfall glycoprotein . Glycobiology . 9 . 1 . 21–30 . January 1999 . 9884403 . 10.1093/glycob/9.1.21 . free .
• Scolari F, Puzzer D, Amoroso A, Caridi G, Ghiggeri GM, Maiorca R, Aridon P, De Fusco M, Ballabio A, Casari G . 6 . Identification of a new locus for medullary cystic disease, on chromosome 16p12 . American Journal of Human Genetics . 64 . 6 . 1655–60 . June 1999 . 10330352 . 1377908 . 10.1086/302414 .
• Kamatani N, Moritani M, Yamanaka H, Takeuchi F, Hosoya T, Itakura M . Localization of a gene for familial juvenile hyperuricemic nephropathy causing underexcretion-type gout to 16p12 by genome-wide linkage analysis of a large family . Arthritis and Rheumatism . 43 . 4 . 925–9 . April 2000 . 10765940 . 10.1002/1529-0131(200004)43:4<925::AID-ANR26>3.0.CO;2-B . 10.1.1.542.8350 .
• Pirulli D, Puzzer D, De Fusco M, Crovella S, Amoroso A, Scolari F, Viola BF, Maiorca R, Caridi G, Savoldi S, Ghiggeri G, Casari G . 6 . 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 . 2002 . 11730273 .
• Menozzi FD, Debrie AS, Tissier JP, Locht C, Pethe K, Raze D . Interaction of human Tamm-Horsfall glycoprotein with Bordetella pertussis toxin . Microbiology . 148 . Pt 4 . 1193–1201 . April 2002 . 11932463 . 10.1099/00221287-148-4-1193 . free .
• Zbikowska HM, Soukhareva N, Behnam R, Lubon H, Hammond D, Soukharev S . Uromodulin promoter directs high-level expression of biologically active human alpha1-antitrypsin into mouse urine . The Biochemical Journal . 365 . Pt 1 . 7–11 . July 2002 . 11982485 . 1222653 . 10.1042/BJ20020643 .
• Hart TC, Gorry MC, Hart PS, Woodard AS, Shihabi Z, Sandhu J, Shirts B, Xu L, Zhu H, Barmada MM, Bleyer AJ . 6 . 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 . December 2002 . 12471200 . 1757206 . 10.1136/jmg.39.12.882 .

External links

• GeneReviews/NCBI/NIH/UW entry on UMOD-Related Kidney Disease Includes: Familial Juvenile Hyperuricemic Nephropathy, Medullary Cystic Kidney Disease 2
• OMIM entries on UMOD-Related Kidney Disease Includes: Familial Juvenile Hyperuricemic Nephropathy, Medullary Cystic Kidney Disease 2
• Tamm–Horsfall protein deposition

Notes and References

1. Jeanpierre C, Whitmore SA, Austruy E, Cohen-Salmon M, Callen DF, Junien C . Chromosomal assignment of the uromodulin gene (UMOD) to 16p13.11 . Cytogenetics and Cell Genetics . 62 . 4 . 185–7 . Mar 1993 . 8382593 . 10.1159/000133470 .
2. Web site: Entrez Gene: UMOD uromodulin (uromucoid, Tamm–Horsfall glycoprotein).
3. Lau WH, Leong WS, Ismail Z, Gam LH . Qualification and application of an ELISA for the determination of Tamm Horsfall protein (THP) in human urine and its use for screening of kidney stone disease . International Journal of Biological Sciences . 4 . 4 . 215–22 . August 2008 . 18695745 . 2500153 . 10.7150/ijbs.4.215 .
4. Nagaraj N, Mann M . Quantitative analysis of the intra- and inter-individual variability of the normal urinary proteome . Journal of Proteome Research . 10 . 2 . 637–45 . February 2011 . 21126025 . 10.1021/pr100835s .
5. Bokhove M, Nishimura K, Brunati M, Han L, de Sanctis D, Rampoldi L, Jovine L . A structured interdomain linker directs self-polymerization of human uromodulin . Proc. Natl. Acad. Sci. U.S.A. . 113 . 6 . 1552–1557 . 2016 . 26811476 . 10.1073/pnas.1519803113 . 4760807 . 2016PNAS..113.1552B . free .
6. Stsiapanava A, Xu C, Nishio S, Han L, Yamakawa N, Carroni M, Tunyasuvunakool K, Jumper J, de Sanctis D, Wu B, Jovine L . 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 . 2022 . 35273390 . 10.1038/s41594-022-00729-3 . 8930769 . free .
7. Jovine L, Qi H, Williams Z, Litscher E, de Sanctis D, Wassarman PM . The ZP domain is a conserved module for polymerization of extracellular proteins . Nat. Cell Biol. . 4 . 6 . 457–461 . 2002 . 12021773 . 10.1038/ncb802 . 11575790 .
8. 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 . Cryo-EM structure of native human uromodulin, a zona pellucida module polymer . EMBO J. . e106807 . 2020 . 39 . 24 . 33196145 . 10.15252/embj.2020106807 . 7737619 . free .
9. Weiss GL, Stanisich JJ, Sauer MM, Lin CW, Eras J, Zyla DS, Trück J, Devuyst O, Aebi M, Pilhofer M, Glockshuber R . Architecture and function of human uromodulin filaments in urinary tract infections . Science . New York, N.Y. . 369 . 6506 . 1005–1010 . 2020 . 32616672 . 10.1126/science.aaz9866 . 220328267 . free . 20.500.11850/438598 . free .
10. Stanisich JJ, Zyla DS, Afanasyev P, Xu J, Kipp A, Olinger E, Devuyst O, Pilhofer M, Boehringer D, Glockshuber R . The cryo-EM structure of the human uromodulin filament core reveals a unique assembly mechanism . eLife . 9. e60265 . 2020 . 32815518 . 10.7554/eLife.60265 . 7486124 . free .
11. Bachmann S, Mutig K, Bates J, Welker P, Geist B, Gross V, Luft FC, Alenina N, Bader M, Thiele BJ, Prasadan K, Raffi HS, Kumar S . 6 . Renal effects of Tamm-Horsfall protein (uromodulin) deficiency in mice . American Journal of Physiology. Renal Physiology . 288 . 3 . F559-67 . March 2005 . 15522986 . 10.1152/ajprenal.00143.2004 . 33703271 .
12. El-Achkar TM, Wu XR, Rauchman M, McCracken R, Kiefer S, Dagher PC . Tamm-Horsfall protein protects the kidney from ischemic injury by decreasing inflammation and altering TLR4 expression . American Journal of Physiology. Renal Physiology . 295 . 2 . F534-44 . August 2008 . 18495803 . 5504389 . 10.1152/ajprenal.00083.2008 .
13. Vizjak A, Trnacević S, Ferluga D, Halilbasić A . Renal function, protein excretion, and pathology of Balkan endemic nephropathy. IV. Immunohistology . Kidney International . 34 . S68-74 . November 1991 . 1762338 .
14. Book: Abbas AK, Gerber R, Mitchell RS, Kumar V, Fausto N . Pocket companion to Robbins and Cotran Pathologic Basis of Disease . 7th . Saunders, Elsevier . Philadelphia, Pa . 2006 . 353 . 0-7216-0265-7 . registration .
15. Book: Kumar V, Abbas AK, Fauso N, Mitchell R . Robbins Basic Patholog . Aster JC . The Hematopoietic and Lymphoid Systems . 2007 . Saunders/Elsevier . Philadelphia, PA . 978-1-4160-2973-1 . 455 . 8th .
16. Tamm I, Horsfall FL . A mucoprotein derived from human urine which reacts with influenza, mumps, and Newcastle disease viruses . The Journal of Experimental Medicine . 95 . 1 . 71–97 . January 1952 . 14907962 . 2212053 . 10.1084/jem.95.1.71 .