It took me until just recently to realize this, but the Tamm-Horsfall protein and uromodulin are two names for the same gene. As we all know, Tamm-Horsfall protein (discovered by Tamm and Horsfall in 1950) is the most abundant protein in normal urine and forms the transparent matrix of hyaline casts. It is synthesized as a membrane protein which is attached to the apical membrane by a GPI-anchor facing the tubular lumen; when cleaved off it is excreted in the urine. Casts only form in the distal tubule & collecting duct, not in the proximal tubule. What is its function?
1. Tamm-Horsfall protein acts as a constitutive inhibitor of calcium-based stone formation. Mice deficient for Tamm-Horsfall protein show an increased tendency towards nephrolithiasis.
2. Tamm-Horsfall protein acts to prevent urinary tract infection. There is some data that certain strains of E. coli may be bound by Tamm-Horsfall protein; once cleaved this could represent a means of eliminating the organism from the urinary tract.
3. Mutations in Tamm-Horsfall protein cause the autosomal dominant disorder medullary cystic kidney disease type 2 (MCDK2) as well as the disorder familial juvenile hyperuricemic nephropathy (FJHN) . This is a pediatric-onset disease characterized by hyperuricemia, gout, and progressive renal failure. Interestingly it appears that the pathophysiologic mechanism here is that mutations in this gene lead to defects in protein folding and intracellular deposition of mutant Tamm-Horsfall protein.
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