Uromodulin (UMOD), also known as Tamm–Horsfall protein (THP), is a Zona pellucida-like domain-containing glycoprotein 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. 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 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 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 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)