Tamm–Horsfall protein
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Uromodulin (UMOD), also known as Tamm–Horsfall protein (THP), is a Zona pellucida-like domain-containing
glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
that in humans is encoded by the ''UMOD'' gene. Uromodulin is the most abundant protein excreted in ordinary 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.


Protein

THP is a GPI-anchored
glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
. It is not derived from blood plasma but is produced by the
thick ascending limb of the loop of Henle Within the nephron of the kidney, the ascending limb of the loop of Henle is a segment of the heterogenous loop of Henle downstream of the descending limb, after the sharp bend of the loop. This part of the renal tubule is divided into a thin a ...
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. 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). It is the matrix of
urinary casts Urinary casts are microscopic cylindrical structures produced by the kidney and present in the urine in certain disease states. They form in the distal convoluted tubule and collecting ducts of nephrons, then dislodge and pass into the urine, wher ...
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 Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...
-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. The ZP domain polymerizes into filaments, with protruding arms that correspond to the EGF I-III domains and the decoy module.


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. 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. A role in bacterial binding and sequestration is suggested by studies showing that '' Escherichia coli'' which express MS (mannose-sensitive)
pili Pili may refer to: Common names of plants * ''Canarium ovatum'', a Philippine tree that is a source of the pili nut * ''Heteropogon contortus'', a Hawaiian grass used to thatch structures Places * Pili, Camarines Sur, is a municipality in the ...
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.


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. Antibodies to Tamm–Horsfall protein have been seen in various forms of
nephritis Nephritis is inflammation of the kidneys and may involve the glomeruli, tubules, or interstitial tissue surrounding the glomeruli and tubules. It is one of several different types of nephropathy. Types * Glomerulonephritis is inflammation of th ...
(e.g.,
Balkan nephropathy Balkan endemic nephropathy (BEN) is a form of interstitial nephritis causing kidney failure. It was first identified in the 1920s among several small, discrete communities along the Danube River and its major tributaries, in the modern countries of ...
), however, it remains unclear whether there is any pathophysiologic relevance to these findings. 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 Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...
, 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. This is known as myeloma cast nephropathy.


History

The
glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
was first purified in 1952 by Igor Tamm and
Frank Horsfall Frank Lappin Horsfall, Jr. (Seattle, December 14, 1906 – New York City, February 19, 1971) was an American microbiologist specializing in pathology. He worked at the Rockefeller Institute, New York, from 1934 to 1960 and in the early 1950s ran ...
from the urine of healthy individuals. It was later detected in the urine of all mammals studied.


References


Further reading

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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


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