A novel homozygous UMOD mutation reveals gene dosage effects on uromodulin processing and urinary excretion

Abstract

Heterozygous mutations in UMOD encoding the urinary protein uromodulin are the most common genetic cause of autosomal dominant tubulointerstitial kidney disease (ADTKD). We describe the exceptional case of a patient from a consanguineous family carrying a novel homozygous UMOD mutation (p.C120Y) affecting a conserved cysteine residue within the EGF-like domain III of uromodulin. Comparison of heterozygote and homozygote mutation carriers revealed a gene dosage effect with unprecedented low levels of uromodulin and aberrant uromodulin fragments in the urine of the homozygote proband. Despite an amplified biological effect of the homozygote mutation, the proband did not show a strikingly more severe clinical evolution nor was the near absence of urinary uromodulin associated with urinary tract infections or kidney stones.

The Use of Genomics to Drive Kidney Disease Drug Discovery and Development

“…Despite the seven decades of work on Tamm-Horsfall protein, neither the cellular target nor the downstream effectors of UMOD action have been definitively identified. Biologic targeting using UMOD itself as a therapeutic would be complicated by its large size and requirement of proper folding and maintenance of 24 cysteine-cysteine disulfide bonds (50). Similar experiences complicate targeting genetic variants associated with type 2 diabetes mellitus and Alzheimer disease GWAS in which TCF7L2 (51,52) and ApoE4 (53) polymorphisms respectively strongly associate, yet the biologic mechanisms underlying their genetic association with disease remains frustratingly obscure.…”

Susceptibility genes of hyperuricemia and gout

“…Its expression is regulated by transcription factors such as SP1, TP3, POU2F1, STAT3 and RARA [ 105 ]. Researchers found that more than 90% of UMOD gene mutations occurred in exons 3 and 4 [ 27 ]. This mutation causes autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD), also known as familial juvenile HUA nephropathy (FJHN) [ 27 , 106 ].…”

“…Researchers found that more than 90% of UMOD gene mutations occurred in exons 3 and 4 [ 27 ]. This mutation causes autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD), also known as familial juvenile HUA nephropathy (FJHN) [ 27 , 106 ]. This disease is an autosomal dominant disease, which is rare in children.…”

“…Although it is related to ADTKD, the affected members do not seem to show HUA and gout [ 109 ]. In addition, homozygous mutations in UMOD gene seem to be more prone to early-onset gout [ 27 ]. The study found that the methylation level of UMOD in peripheral blood was related to the risk of gout, and its methylation evaluation could predict the risk of gout [ 110 ].…”

Preoperative levels of urinary uromodulin predict acute kidney injury after pediatric cardiopulmonary bypass surgery

“…It is a glycoprotein that is expressed in the thick ascending limb (TAL) of the Loop of Henle and was first purified by Igor Tamm and Frank Horsfall in 1952 [13–15]. Mutations in the UMOD gene are associated with medullary cystic kidney disease and autosomal dominant tubulointerstitial kidney disease [16, 17]. In healthy kidneys, UMOD is thought to have a role in salt transport in the tubules, innate immunity and protection against kidney stones [18].…”