Uromodulin (UMOD), also known as Tamm–Horsfall protein (THP), is a
Zona pellucida-like domain
The Zona pellucida-like domain (ZP domain / ZP-like domain / ZP module) is a large protein region of about 260 amino acids. It has been recognised in a variety of receptor-like eukaryotic glycoproteins. All of these molecules are mosaic proteins ...
-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
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
Uromodulin is the most abundant protein excreted in ordinary
urine
Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra.
Cel ...
.
Gene
The human UMOD gene is located on
chromosome 16
Chromosome 16 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 16 spans about 90 million base pairs (the building material of DNA) and represents just under 3% of the total DNA in cell ...
. 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
Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intra ...
but is produced by the
thick ascending limb of the loop of Henle of the mammalian
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
. While the monomeric molecule has a MW of approximately 85
kDa
The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...
, it is physiologically present in urine in large aggregates of up to several million
Da.
When this
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
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
The EGF-like domain is an evolutionary conserved protein domain, which derives its name from the epidermal growth factor where it was first described. It comprises about 30 to 40 amino-acid residues and has been found in a large number of mostl ...
(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
An ectodomain is the domain of a membrane protein that extends into the extracellular space (the space outside a cell). Ectodomains are usually the parts of proteins that initiate contact with surfaces, which leads to signal transduction.A notable ...
of its
glycophosphatidylinositol
Glycosylphosphatidylinositol (), or glycophosphatidylinositol, or GPI in short, is a phosphoglyceride that can be attached to the C-terminus of a protein during posttranslational modification. The resulting GPI-anchored proteins play key roles i ...
-anchored counterpart that is situated on the
luminal cell surface of the
loop of Henle
In the kidney, the loop of Henle () (or Henle's loop, Henle loop, nephron loop or its Latin language, Latin counterpart ''ansa nephroni'') is the portion of a nephron that leads from the proximal convoluted tubule to the distal convoluted tubule. ...
. 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 infection
A urinary tract infection (UTI) is an infection that affects part of the urinary tract. When it affects the lower urinary tract it is known as a bladder infection (cystitis) and when it affects the upper urinary tract it is known as a kidney ...
s 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
''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
'' 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.
Clinical significance
Uropontin, nephrocalcin and uromodulin (this protein) are the three known urinary glycoproteins that affect the formation of calcium-containing
kidney stones
Kidney stone disease, also known as nephrolithiasis or urolithiasis, is a crystallopathy where a solid piece of material (kidney stone) develops in the urinary tract. Kidney stones typically form in the kidney and leave the body in the urine s ...
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
Hyperuricaemia or hyperuricemia is an abnormally high level of uric acid in the blood. In the pH conditions of body fluid, uric acid exists largely as urate, the ion form. Serum uric acid concentrations greater than 6 mg/dL for females, 7&nbs ...
,
gout
Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot and swollen joint, caused by deposition of monosodium urate monohydrate crystals. Pain typically comes on rapidly, reaching maximal intensit ...
, 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
Bence Jones protein is a monoclonal globulin protein or immunoglobulin light chain found in the urine, with a molecular weight of 22–24 kDa. Detection of Bence Jones protein may be suggestive of multiple myeloma or Waldenström's macroglobuli ...
, but often also contain Tamm–Horsfall protein.
This is known as
myeloma cast nephropathy
Myeloma cast nephropathy, also referred to as light-chain cast nephropathy, is the formation of plugs (urinary casts) in the kidney tubules from free immunoglobulin light chains leading to kidney failure in the context of multiple myeloma. It is ...
.
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
Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra.
Cel ...
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
{{DEFAULTSORT:Tamm-Horsfall protein
Glycoproteins