Uromodulin (UMOD),Tamm-Horsfall protein (THP), is a
zona pellucida-like domain-containing
glycoprotein that in humans is encoded by the ''UMOD''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
Uromodulin is the most abundant protein excreted in ordinary
urine
Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...
.
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. 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.
When this
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
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 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.
[ ][ ] 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 n ...
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
''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Escherichia'' that is commonly fo ...
'' 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 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
Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of pain in a red, tender, hot, and Joint effusion, swollen joint, caused by the deposition of needle-like crystals of uric acid known as monosodium urate crysta ...
, and progressive kidney failure.
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.
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 antibody, antibodies. Often, no symptoms are noticed initially. As it progresses, bone ...
, 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.
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.
It was later detected in the
urine
Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...
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