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

Abstract

The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare, large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD) while common, low-effect variants strongly associate with kidney function and risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in gnomAD with MAF ranging from 10-5 to 10-3. Among them, the missense variant p.Thr62Pro is detected in ~1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD and is associated with kidney failure in the 100,000 Genomes Project (OR 3.99; 1.84-8.98) and the UK Biobank (OR 4.12; 1.32-12.85). Compared to canonical ADTKD mutations, the p.Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD, intermediate reduction of urinary UMOD levels, in line with an intermediate trafficking defect in vitro. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD-associated kidney diseases and provides novel insights into the mechanisms of ADTKD and the genetic architecture of CKD.

Allelic and Gene Dosage Effects Involving Uromodulin Aggregates Drive Autosomal Dominant Tubulointerstitial Kidney Disease

“…inflammation, interstitial fibrosis and kidney failure in the Umod R186S kidneys, contrasting with an increased expression of genes involved in protein folding in the Umod C171Y kidneys. The changes driven by the R186S mutation are in line with the emerging role of ER proteostasis in kidney disease, as evidenced for intermediate-effect size variants in UMOD (30) and for mutations in MUC1 also associated with ADTKD (31). Furthermore, the strong induction of lipocalin-2 (LCN2) in the R186S kidneys may provide a link between ER stress, UPR, inflammation and fibrosis, as LCN2 is a known homing factor for inflammatory cells and an active player in kidney disease progression (32, 33).…”

Diverse molecular causes of unsolved autosomal dominant tubulointerstitial kidney diseases

“…The variant classification by ACMG and the evaluation by the CADD score are displayed (see Methods section). Asterisk in family A-31 marks the segregating UMOD T62P variant, which was already reported in Ekici et al21 and further studied in Olinger et al48 Structural impacts of COL4A5 and INF2 missense mutations are shown in Supplementary FigureS1. See Supplementary TableS3for further validation of the diagnostic copy number variants (PAX2, SALL1, and PKD2) and the splice site variant in COL4A4.…”

“…Several variants were excluded by segregation, gene curation (PKD1), or lacking splice effect in mRNA extracted from patient-derived skin fibroblasts (FN1). Table 4 21,48 lists all of the detected variants from the nephrome analysis and the conclusions drawn by specific criteria. The classic and atypical features of respective index patients in these families are summarized in Supplementary Table S2.…”

Autosomal dominant tubulointerstitial kidney disease: A review

“…In addition, a p.Arg178Pro pathogenic variant has been identified in 13 US families with a median age of ESRD of 49.7 years. The p.Thr62Pro variant, which has been found in unaffected individuals as well as some individuals with CKD, has an intermediate effect on risk for CKD and is not a sole cause of ADTKD‐ UMOD (Olinger et al, 2022). In addition to these pathogenic variants, given the autosomal dominant inheritance, age of end‐stage kidney disease after child‐bearing age in most individuals, and the difficulties in diagnosing this condition, there are a number of distantly related families that share the same pathogenic variant.…”