Genetic and Clinical Predictors of Age of ESKD in Individuals With Autosomal Dominant Tubulointerstitial Kidney Disease Due to UMOD Mutations

Abstract

Introduction Autosomal dominant tubulo-interstitial kidney disease due to UMOD mutations (ADTKD- UMOD ) is a rare condition associated with high variability in the age of end-stage kidney disease (ESKD). The minor allele of rs4293393, located in the promoter of the UMOD gene, is present in 19% of the population and downregulates uromodulin production by approximately 50% and might affect the age of ESKD. The goal of this study was to better understand the genetic and clinical characteristics of ADTKD- UMOD and to perform a Mendelian randomization study to determine if the minor allele of rs4293393 was associated with better kidney survival. Methods An international group of collaborators collected clinical and genetic data on 722 affected individuals from 249 families with 125 mutations, including 28 new mutations. The median age of ESKD was 47 years. Men were at a much higher risk of progression to ESKD (hazard ratio 1.78, P < 0.001). Results The allele frequency of the minor rs4293393 allele was only 11.6% versus the 19% expected ( P < 0.01), resulting in Hardy-Weinberg disequilibrium and precluding a Mendelian randomization experiment. An in vitro score reflecting the severity of the trafficking defect of uromodulin mutants was found to be a promising predictor of the age of ESKD. Conclusion We report the clinical characteristics associated with 125 UMOD mutations. Male gender and a new in vitro score predict age of ESKD.

An intermediate effect size variant in UMOD confers risk for chronic kidney disease

“…Furthermore, the in vitro data suggest that additional stressors may be required to induce cell toxicity, possibly reflected by the incomplete penetrance and later onset of disease in pThr62Pro carriers. These findings also corroborate the recent evidence that, in ADTKD- UMOD , the severity of the mutant UMOD trafficking defect correlates with disease severity (20). Further in vitro and in silico evidence substantiate the specific effect of the proline substitution on UMOD folding and ER exit, possibly by impacting on the neighbouring disulphide bond, in line with mutagenesis datasets showing missense proline insertions being associated with highest predicted damage (32).…”

“…In this setting a typical ADTKD UMOD mutant as p.Cys150Ser is fully retained in the ER, as evidenced by the absence of the mature form, thus demonstrating an intermediate phenotype for p.Thr62Pro isoform between wild-type UMOD and ADTKD mutants. The effect of p.Thr62Pro on protein maturation was confirmed using pulse chase experiments in stably transfected HEK293 cells: p.Thr62Pro UMOD showed an intermediate cellular phenotype between wild-type and p.Cys317Tyr UMOD (a reference ADTKD mutant (20)), with increased amount of immature UMOD at 2h after chase (Figure 2B). Consistent with an intermediate phenotype, colocalization of UMOD with a plasma membrane marker is decreased for p.Thr62Pro compared to wild-type UMOD and to the two variants p.Leu180Val and p.Thr469Met, while it is increased compared with p.Cys150Ser (Figure 2C).…”

“…Data presented here were derived from the following resources available in the public domain: The Genome Aggregation Database v2.1.1 (https://gnomad.broadinstitute.org/) and Ensembl (release 100): (https://www.ensembl.org/index.html). The International ADTKD Cohort as well as the UMOD in vitro scoring have been published (11,20). Overlapping UMOD variants with frequencies in the general population, number of ADTKD families and in silico pathogenicity scores.…”

Mitochondriopathy Manifesting as Inherited Tubulointerstitial Nephropathy Without Symptomatic Other Organ Involvement

“…Genetic testing for UMOD mutations was performed by Charles University by candidate gene Sanger sequencing (Prague, Czech Republic) (5). Importantly, no mutations were detected in either genes, further supporting the diagnosis of a mitochondrially-inherited kidney disease.…”

Emerging Insights Into Chronic Renal Disease Pathogenesis in Hypertension From Human and Animal Genomic Studies

“…Rare variants in uromodulin have previously been associated with renal disease, notably autosomal dominant tubulointerstitial nephropathy. 60 However, GWAS association between UMOD variation and loss of renal function has been attributed to a common variation representing the highly prevalent ancestral allele that modifies UMOD gene expression. 61 , 62 The genetic and pathogenic insights into UMOD function and variation have been recently thoroughly reviewed.…”