Tamm–Horsfall protein

2018-08-14T09:01:00Z

2A01:CB14:1E0:9900:4D23:4B2C:BBC8:D9B6: /* 3D structure */

{{Use dmy dates|date=May 2012}}
{{Infobox_gene}}
The '''Tamm–Horsfall glycoprotein''' ('''THP'''), also known as '''uromodulin''', is a [[glycoprotein]] that in humans is encoded by the ''UMOD'' [[gene]].<ref name="pmid8382593">{{cite journal | vauthors=Jeanpierre C, Whitmore SA, Austruy E, Cohen-Salmon M, Callen DF, Junien C | title = Chromosomal assignment of the uromodulin gene (UMOD) to 16p13.11 | journal=Cytogenet Cell Genet | volume = 62 | issue = 4 | pages = 185–7 |date=Mar 1993 | pmid = 8382593 | pmc = | doi =10.1159/000133470 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: UMOD uromodulin (uromucoid, Tamm–Horsfall glycoprotein)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7369}}</ref> Uromodulin is the most abundant protein excreted in ordinary [[urine]].<ref name="Lau_2008">{{cite journal | vauthors=Lau WH, Leong WS, Ismail Z, Gam LH | title = 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 | journal=Int. J. Biol. Sci. | volume = 4 | issue = 4 | pages = 215–22 | year = 2008 | pmid = 18695745 | pmc = 2500153 | doi=10.7150/ijbs.4.215}}</ref>

== 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.<ref name="entrez"/>

== Protein ==

THP is a [[glycophosphatidylinositol|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 [[Atomic mass unit|kDa]], it is physiologically present in urine in large aggregates of up to several million [[Dalton (unit)|Da]].<ref name="Lau_2008"/> 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).<ref name="Nagaraj_Mann_2011">{{cite journal | vauthors = Nagaraj N, Mann M | title = Quantitative analysis of the intra- and inter-individual variability of the normal urinary proteome | journal = J. Proteome Res. | volume = 10 | issue = 2 | pages = 637–45 |date=February 2011 | pmid = 21126025 | doi = 10.1021/pr100835s }}</ref> It is the matrix of [[urinary casts]] derived from the secretion of renal tubular cells.

== 3D structure ==

The crystal structure of UMOD ({{PDB|4WRN}}) was reported In January 2016 by researchers at [[Karolinska Institutet]], in collaboration with groups at San Raffaele Scientific Institute and [[European Synchrotron Radiation Facility]].<ref name="pmid26811476">{{cite journal | vauthors=Bokhove M, Nishimura K, Brunati M, Han L, de Sanctis D, Rampoldi L, Jovine L | title = A structured interdomain linker directs self-polymerization of human uromodulin | journal=Proc. Natl. Acad. Sci. U.S.A. | volume = 113 | issue = 6 | pages = 1552–1557 |date=2016 | pmid = 26811476 | doi = 10.1073/pnas.1519803113 | pmc = 4760807 }} {{PDB|4WRN}}</ref>

== Function ==

Uromodulin excretion in urine follows proteolytic cleavage of the [[ectodomain]] of its [[glycophosphatidylinositol]]-anchored counterpart that is situated on the [[Lumen (anatomy)|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.<ref name="entrez"/>

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.<ref name="pmid15522986">{{cite journal | vauthors=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 | title = Renal effects of Tamm-Horsfall protein (uromodulin) deficiency in mice | journal=Am. J. Physiol. Renal Physiol. | volume = 288 | issue = 3 | pages = F559–67 | year = 2005 | pmid = 15522986 | doi = 10.1152/ajprenal.00143.2004 }}</ref> A role in bacterial binding and sequestration is suggested by studies showing that ''[[Escherichia coli]]'' which express MS (mannose-sensitive) [[Pilus|pili]] or [[fimbria (bacteriology)|fimbria]]e (also ''fimbria'', from the Latin word for "fringe") can be trapped by Tamm–Horsfall protein via its mannose-containing side chains.<ref name="Lau_2008" /> THP may also be important in protection from kidney injury by down-regulating inflammation.<ref>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. Am J Physiol Renal Physiol. 2008 Aug;295(2):F534-44. doi: 10.1152/ajprenal.00083.2008. Epub 2008 May 21. {{PMID|18495803}}</ref>

== 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.<ref name="Lau_2008" />

Defects in this gene are associated with the autosomal dominant renal disorders [[medullary cystic kidney disease|medullary cystic kidney disease-2]] (MCKD2) and familial juvenile hyperuricemic nephropathy (FJHN). These disorders are characterized by juvenile onset of [[hyperuricemia]], [[gout]], and progressive kidney failure.<ref name="entrez"/>

Antibodies to Tamm–Horsfall protein have been seen in various forms of [[nephritis]] (e.g., [[Danubian endemic familial nephropathy|Balkan nephropathy]]), however, it remains unclear whether there is any pathophysiologic relevance to these findings.<ref name="pmid1762338">{{cite journal | vauthors=Vizjak A, Trnacević S, Ferluga D, Halilbasić A | title = Renal function, protein excretion, and pathology of Balkan endemic nephropathy. IV. Immunohistology | journal=Kidney Int. Suppl. | volume = 34 | pages = S68–74 |date=November 1991 | pmid = 1762338 }}</ref>

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 contain Tamm–Horsfall protein.<ref name="isbn0-7216-0265-7">{{cite book | vauthors=Abbas AK, Gerber R, Mitchell RS, Kumar V, Fausto N | title = Pocket companion to Robbins and Cotran Pathologic Basis of Disease | edition = 7th | publisher=Saunders, Elsevier | location = Philadelphia, Pa | year = 2006 | origyear = | pages = 353 | isbn = 0-7216-0265-7 }}</ref><ref name=Robbins>{{Cite book | veditors = Kumar V, Abbas AK, Fauso N, Mitchell R | title = Robbins Basic Patholog | author = Aster JC | chapter = The Hematopoietic and Lymphoid Systems | year = 2007 | publisher = Saunders/Elsevier | location = Philadelphia, PA | isbn = 1-4160-2973-7 | page = 455 | edition = 8th }}</ref>

== History ==
The [[glycoprotein]] was first purified in 1952 by Igor Tamm and [[Frank Horsfall]] from the urine of healthy individuals.<ref name="pmid14907962">{{cite journal | vauthors=Tamm I, Horsfall FL | title = A mucoprotein derived from human urine which reacts with influenza, mumps, and Newcastle disease viruses | journal=J. Exp. Med. | volume = 95 | issue = 1 | pages = 71–97 |date=January 1952 | pmid = 14907962 | doi = 10.1084/jem.95.1.71 | pmc = 2212053 }}</ref> It was later detected in the [[urine]] of all mammals studied.

== References ==
{{reflist|35em}}

== Further reading ==
{{refbegin|35em}}
*{{cite journal |vauthors=Scolari F, Viola BF, Ghiggeri GM, etal |title=Towards the identification of (a) gene(s) for autosomal dominant medullary cystic kidney disease. |journal=J. Nephrol. |volume=16 |issue= 3 |pages= 321–8 |year= 2003 |pmid= 12832729 }}
*{{cite journal |vauthors=Rindler MJ, Naik SS, Li N, etal |title=Uromodulin (Tamm-Horsfall glycoprotein/uromucoid) is a phosphatidylinositol-linked membrane protein. |journal=J. Biol. Chem. |volume=265 |issue= 34 |pages= 20784–9 |year= 1991 |pmid= 2249987 }}
*{{cite journal | vauthors=Muchmore AV, Decker JM |title=Uromodulin: a unique 85-kilodalton immunosuppressive glycoprotein isolated from urine of pregnant women. |journal=Science |volume=229 |issue= 4712 |pages= 479–81 |year= 1985 |pmid= 2409603 |doi=10.1126/science.2409603 }}
*{{cite journal |vauthors=Pennica D, Kohr WJ, Kuang WJ, etal |title=Identification of human uromodulin as the Tamm-Horsfall urinary glycoprotein. |journal=Science |volume=236 |issue= 4797 |pages= 83–8 |year= 1987 |pmid= 3453112 |doi=10.1126/science.3453112 }}
*{{cite journal |vauthors=Hession C, Decker JM, Sherblom AP, etal |title=Uromodulin (Tamm-Horsfall glycoprotein): a renal ligand for lymphokines. |journal=Science |volume=237 |issue= 4821 |pages= 1479–84 |year= 1987 |pmid= 3498215 |doi=10.1126/science.3498215 }}
*{{cite journal |vauthors=Prasadan K, Bates J, Badgett A, etal |title=Nucleotide sequence and peptide motifs of mouse uromodulin (Tamm-Horsfall protein)--the most abundant protein in mammalian urine. |journal=Biochim. Biophys. Acta |volume=1260 |issue= 3 |pages= 328–32 |year= 1995 |pmid= 7873609 |doi=10.1016/0167-4781(94)00240-4}}
*{{cite journal | vauthors=Huang ZQ, Kirk KA, Connelly KG, Sanders PW |title=Bence Jones proteins bind to a common peptide segment of Tamm-Horsfall glycoprotein to promote heterotypic aggregation. |journal=J. Clin. Invest. |volume=92 |issue= 6 |pages= 2975–83 |year= 1994 |pmid= 8254051 |doi=10.1172/JCI116920 | pmc=288501 }}
*{{cite journal | vauthors=Rhodes DC, Hinsman EJ, Rhodes JA |title=Tamm-Horsfall glycoprotein binds IgG with high affinity. |journal=Kidney Int. |volume=44 |issue= 5 |pages= 1014–21 |year= 1994 |pmid= 8264130 |doi=10.1038/ki.1993.343 }}
*{{cite journal |vauthors=Fukushima K, Watanabe H, Takeo K, etal |title=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. |journal=Arch. Biochem. Biophys. |volume=304 |issue= 1 |pages= 144–53 |year= 1993 |pmid= 8323280 |doi= 10.1006/abbi.1993.1332 }}
*{{cite journal | vauthors=Thomas DB, Davies M, Peters JR, Williams JD |title=Tamm Horsfall protein binds to a single class of carbohydrate specific receptors on human neutrophils. |journal=Kidney Int. |volume=44 |issue= 2 |pages= 423–9 |year= 1993 |pmid= 8397318 |doi=10.1038/ki.1993.260 }}
*{{cite journal | vauthors=Badgett A, Kumar S |title=Phylogeny of Tamm-Horsfall protein. |journal=Urol. Int. |volume=61 |issue= 2 |pages= 72–5 |year= 1999 |pmid= 9873244 |doi=10.1159/000030292 }}
*{{cite journal | vauthors=van Rooijen JJ, Voskamp AF, Kamerling JP, Vliegenthart JF |title=Glycosylation sites and site-specific glycosylation in human Tamm-Horsfall glycoprotein. |journal=Glycobiology |volume=9 |issue= 1 |pages= 21–30 |year= 1999 |pmid= 9884403 |doi=10.1093/glycob/9.1.21 }}
*{{cite journal |vauthors=Scolari F, Puzzer D, Amoroso A, etal |title=Identification of a new locus for medullary cystic disease, on chromosome 16p12. |journal=Am. J. Hum. Genet. |volume=64 |issue= 6 |pages= 1655–60 |year= 1999 |pmid= 10330352 |doi=10.1086/302414 | pmc=1377908 }}
*{{cite journal |vauthors=Kamatani N, Moritani M, Yamanaka H, etal |title=Localization of a gene for familial juvenile hyperuricemic nephropathy causing underexcretion-type gout to 16p12 by genome-wide linkage analysis of a large family. |journal=Arthritis Rheum. |volume=43 |issue= 4 |pages= 925–9 |year= 2000 |pmid= 10765940 |doi= 10.1002/1529-0131(200004)43:4<925::AID-ANR26>3.0.CO;2-B }}
*{{cite journal |vauthors=Pirulli D, Puzzer D, De Fusco M, etal |title=Molecular analysis of uromodulin and SAH genes, positional candidates for autosomal dominant medullary cystic kidney disease linked to 16p12. |journal=J. Nephrol. |volume=14 |issue= 5 |pages= 392–6 |year= 2002 |pmid= 11730273 }}
*{{cite journal |vauthors=Menozzi FD, Debrie AS, Tissier JP, etal |title=Interaction of human Tamm-Horsfall glycoprotein with Bordetella pertussis toxin. |journal=Microbiology |volume=148 |issue= Pt 4 |pages= 1193–201 |year= 2002 |pmid= 11932463 | doi = 10.1099/00221287-148-4-1193 }}
*{{cite journal |vauthors=Zbikowska HM, Soukhareva N, Behnam R, etal |title=Uromodulin promoter directs high-level expression of biologically active human alpha1-antitrypsin into mouse urine. |journal=Biochem. J. |volume=365 |issue= Pt 1 |pages= 7–11 |year= 2002 |pmid= 11982485 |doi= 10.1042/BJ20020643 | pmc=1222653 }}
*{{cite journal |vauthors=Hart TC, Gorry MC, Hart PS, etal |title=Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. |journal=J. Med. Genet. |volume=39 |issue= 12 |pages= 882–92 |year= 2003 |pmid= 12471200 |doi=10.1136/jmg.39.12.882 | pmc=1757206 }}
*{{cite journal |vauthors=Strausberg RL, Feingold EA, Grouse LH, etal |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 | pmc=139241 }}
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==External links==
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=mckd2 GeneReviews/NCBI/NIH/UW entry on UMOD-Related Kidney Disease Includes: Familial Juvenile Hyperuricemic Nephropathy, Medullary Cystic Kidney Disease 2]
* [https://www.ncbi.nlm.nih.gov/omim/162000,191845,603860,609886,162000,191845,603860,609886 OMIM entries on UMOD-Related Kidney Disease Includes: Familial Juvenile Hyperuricemic Nephropathy, Medullary Cystic Kidney Disease 2]
* [http://www.mcw.edu/chorus/to-go/02058.html Tamm–Horsfall protein deposition]{{Dead link|date=June 2018 |bot=InternetArchiveBot |fix-attempted=no }}

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[[Category:Glycoproteins]]

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Tamm–Horsfall protein