Uromodulin
Template:PBB The Tamm–Horsfall glycoprotein (THP) also known as uromodulin is a glycoprotein that in humans is encoded by the UMOD gene.[1][2] Up to 150 mg/day of uromodulin may be excreted in the urine, making it the most abundant protein in normal urine.
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 68 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. Tamm–Horsfall protein is a high abundant protein in mammalian urine. A recent list of the most abundant proteins in urine has been published (table 1 of[4]), where uromodulin represents the 16th most concentrated one (results based on MSMS determinations). It is the matrix of urinary casts derived from the secretion of renal tubular cells.
Function
Uromodulin excretion in urine following 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.[5] A role in bacterial binding and sequestration is suggested by studies showing that Escherichia coli expressing MS (mannose-sensitive) pili or fimbriae can be trapped by Tamm-Horsfall protein via its mannose-containing side chains.[3]
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.[3]
Defects in this gene are associated with the autosomal dominant renal disorders medullary cystic kidney disease-2 (MCKD2) and familial juvenile hyperuricemic nephropathy (FJHN). These disorders are characterized by juvenile onset of hyperuricemia, gout, and progressive renal 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 (patho-)physiologic relevance to these findings.[6]
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.[7][8]
History
The glycoprotein was first purified by Tamm and Horsfall from the urine of healthy individuals.[9] It was later detected in the urine of all mammals studied.
References
- ^ Jeanpierre C, Whitmore SA, Austruy E, Cohen-Salmon M, Callen DF, Junien C (1993). "Chromosomal assignment of the uromodulin gene (UMOD) to 16p13.11". Cytogenet Cell Genet. 62 (4): 185–7. doi:10.1159/000133470. PMID 8382593.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ a b c d "Entrez Gene: UMOD uromodulin (uromucoid, Tamm–Horsfall glycoprotein)".
- ^ a b c Lau WH, Leong WS, Ismail Z, Gam LH (2008). "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". Int. J. Biol. Sci. 4 (4): 215–22. PMC 2500153. PMID 18695745.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Nagaraj et Mann, 2011, PUBMED link: http://www.ncbi.nlm.nih.gov/pubmed/21126025
- ^ 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 (2005). "Renal effects of Tamm-Horsfall protein (uromodulin) deficiency in mice". Am. J. Physiol. Renal Physiol. 288 (3): F559–67. doi:10.1152/ajprenal.00143.2004. PMID 15522986.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Vizjak A, Trnacević S, Ferluga D, Halilbasić A (1991). "Renal function, protein excretion, and pathology of Balkan endemic nephropathy. IV. Immunohistology". Kidney Int. Suppl. 34: S68–74. PMID 1762338.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Abbas AK, Gerber R, Mitchell RS, Kumar V, Fausto N (2006). Pocket companion to Robbins and Cotran pathologic basis of disease (7th ed.). Philadelphia, Pa: Saunders, Elsevier. p. 353. ISBN 0-7216-0265-7.
{{cite book}}: CS1 maint: multiple names: authors list (link) - ^ Page 455 (Multiple Myeloma) in: Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson. Robbins Basic Pathology. Philadelphia: Saunders. ISBN 1-4160-2973-7.
{{cite book}}: CS1 maint: multiple names: authors list (link) 8th edition. - ^ Tamm I, Horsfall FL (1952). "A mucoprotein derived from human urine which reacts with influenza, mumps, and Newcastle disease viruses". J. Exp. Med. 95 (1): 71–97. doi:10.1084/jem.95.1.71. PMC 2212053. PMID 14907962.
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Further reading
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