Background: Mutations in the uromodulin (UMOD) gene that encodes Tamm-Horsfall protein (THP) cause an autosomal-dominant form of chronic renal failure. We have now investigated effects of UMOD gene mutations on protein expression by quantitatively measuring THP excretion.
Methods: THP excretion was determined by enzyme-linked immunosorbent assay (ELISA) of urine collections obtained from 16 related individuals with a 27 bp deletion in the UMOD gene and seven individuals with other UMOD mutations. THP excretion of 22 control subjects (18 genetically related individuals and four spouses in the UMOD deletion family) was also determined.
Results: The 16 individuals carrying the deletion mutation excreted 5.8 +/- 6.3 mg THP/g creatinine into their urine. The 18 unaffected relatives from the same family excreted 40.8 +/- 9.7 mg THP/g creatinine (P < 0.0001) and the four spouses excreted 43.9 +/- 25.1 mg THP/g creatinine (P < 0.0001 vs. individuals with the deletion mutation). THP excretion of seven individuals with other UMOD gene mutations was also extremely low (range of 0.14 to 5.9 mg THP/g creatinine). All individuals with UMOD mutations had low THP excretion, irrespective of gender, glomerular filtration rate (GFR), or age.
Conclusion: These studies quantitatively show that the autosomal-dominant gene mutations responsible for UMOD-associated kidney disease cause a profound reduction of THP excretion. We speculate that this suppression of normal THP excretion reflects deleterious effects of mutated THP within the kidney. Such effects may also play an important role in the pathogenesis of the progressive renal failure observed in patients with UMOD gene mutations.