Tamm–Horsfall protein

The Tamm–Horsfall glycoprotein (THP), also known as uromodulin, is a is_associated_with::glycoprotein that in humans is encoded by the UMOD is_associated_with::gene. Uromodulin is the most abundant protein excreted in ordinary is_associated_with::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 is_associated_with::glycoprotein. It is not derived from is_associated_with::blood plasma but is produced by the is_associated_with::thick ascending limb of the loop of Henle of the mammalian is_associated_with::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 is_associated_with::protein is concentrated at low pH, it forms a gel. Uromodulin represents the most concentrated protein (results based on MSMS determinations). It is the matrix of is_associated_with::urinary casts derived from the secretion of renal tubular cells.

Function
Uromodulin excretion in urine follows proteolytic cleavage of the ectodomain of its is_associated_with::glycophosphatidylinositol-anchored counterpart that is situated on the luminal cell surface of the is_associated_with::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 is_associated_with::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 is_associated_with::Escherichia coli which express MS (mannose-sensitive) pili or is_associated_with::fimbriae (also fimbria, from the Latin word for "fringe") can be trapped by Tamm–Horsfall protein via its mannose-containing side chains.

Clinical significance
Uropontin, nephrocalcin and uromodulin (this protein) are the three known urinary glycoproteins that affect the formation of calcium-containing is_associated_with::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 familial juvenile hyperuricemic nephropathy (FJHN). These disorders are characterized by juvenile onset of is_associated_with::hyperuricemia, gout, and progressive renal failure.

Antibodies to Tamm–Horsfall protein have been seen in various forms of is_associated_with::nephritis (e.g., Balkan nephropathy), however, it remains unclear whether there is any pathophysiologic relevance to these findings.

In is_associated_with::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 is_associated_with::Bence Jones protein, but often also contain Tamm–Horsfall protein.

Page 455 (Multiple Myeloma) in: 8th edition.

History
The is_associated_with::glycoprotein was first purified by Igor Tamm and is_associated_with::Frank Horsfall from the urine of healthy individuals. It was later detected in the is_associated_with::urine of all mammals studied.