Tamm-Horsfall protein
Encyclopedia
The Tamm-Horsfall glycoprotein (THP) also known as uromodulin is a glycoprotein
that in humans is encoded by the UMOD gene
. Up to 150 mg/dl of uromodulin may be excreted in the urine, making it the most abundant protein in normal urine
.
glycoprotein
. It is not derived from blood plasma
but is produced by the thick ascending limb of the loop of Henle of 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
. 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 ), 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.
-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. 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
expressing MS (mannose-sensitive) pili or fimbriae can be trapped by Tamm-Horsfall protein via its mannose-containing side chains.
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.
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.
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.
was first purified by Tamm and Horsfall from the urine of healthy individuals. It was later detected in the urine
of all mammals studied.
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
that in humans is encoded by the UMOD gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. Up to 150 mg/dl of uromodulin may be excreted in the urine, making it the most abundant protein in normal urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
.
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-anchoredGlycophosphatidylinositol
Glycosylphosphatidylinositol is a glycolipid that can be attached to the C-terminus of a protein during posttranslational modification...
glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
. It is not derived from blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
but is produced by the thick ascending limb of the loop of Henle of mammalian kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
. While the monomeric molecule has a MW of approximately 68 kDa
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
, it is physiologically present in urine in large aggregates of up to several million Da
DA
DA, da, or dA may refer to:* Da , a Tony-winning play by Hugh Leonard* Da , a movie adaptation of the play by Hugh Leonard* Adi Da, a spiritual leader once known as Da Free John, and Da Love-Ananda...
. When this protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
is concentrated at low pH, it forms a gel. Tamm-Horsfall protein is a high abundant protein in mammalian urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
. A recent list of the most abundant proteins in urine has been published (table 1 of ), where uromodulin represents the 16th most concentrated one (results based on MSMS determinations). It is the matrix of urinary casts
Urinary casts
Urinary casts are 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, where they can be detected by microscopy.They form via precipitation...
derived from the secretion of renal tubular cells.
Function
Uromodulin excretion in urine follows proteolytic cleavage of the ectodomain of its glycophosphatidylinositolGlycophosphatidylinositol
Glycosylphosphatidylinositol is a glycolipid that can be attached to the C-terminus of a protein during posttranslational modification...
-anchored counterpart that is situated on the luminal cell surface of the loop of Henle
Loop of Henle
In the kidney, the loop of Henle is the portion of a nephron that leads from the proximal convoluted tubule to the distal convoluted tubule. Named after its discoverer F. G. J...
. Uromodulin may act as a constitutive inhibitor of calcium crystallization in renal fluids. 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
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
expressing MS (mannose-sensitive) pili or fimbriae can be trapped by Tamm-Horsfall protein via its mannose-containing side chains.
Clinical significance
Uropontin, nephrocalcin and uromodulin (this protein) are the 3 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
Medullary cystic kidney disease
Medullary cystic kidney disease is an autosomal dominant kidney disorder characterized by cysts in both kidneys and tubulointerstitial sclerosis leading to end-stage renal disease...
(MCKD2) and familial juvenile hyperuricemic nephropathy (FJHN). These disorders are characterized by juvenile onset of hyperuricemia
Hyperuricemia
Hyperuricemia is a level of uric acid in the blood that is abnormally high. In humans, the upper end of the normal range is 360 µmol/L for women and 400 µmol/L for men.-Causes:...
, gout, and progressive renal failure.
Antibodies to Tamm-Horsfall protein have been seen in various forms of nephritis
Nephritis
Nephritis is inflammation of the nephrons in the kidneys. The word "nephritis" was imported from Latin, which took it from Greek: νεφρίτιδα. The word comes from the Greek νεφρός - nephro- meaning "of the kidney" and -itis meaning "inflammation"....
(e.g., Balkan nephropathy), however, it remains unclear whether there is any (patho-)physiologic relevance to these findings.
In multiple myeloma
Multiple myeloma
Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
, 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
A Bence Jones protein is a monoclonal globulin protein found in the blood or urine, with a molecular weight of 22-24 kDa.Finding this protein is often suggestive of multiple myeloma or Waldenstrom's macroglobulinemia....
, but often also contain Tamm-Horsfall protein.
History
The glycoproteinGlycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
was first purified by Tamm and Horsfall from the urine of healthy individuals. It was later detected in the urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
of all mammals studied.
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