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-impact variants strongly associate with kidney function and the 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, patient samples, and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in the Genome Aggregation Database (gnomAD), with minor allele frequency (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 (odds ratio [OR] = 3.99 [1.84 to 8.98]) and the UK Biobank (OR = 4.12 [1.32 to 12.85). Compared with canonical ADTKD mutations, the p.Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD and an intermediate reduction of urinary uromodulin levels, in line with an intermediate trafficking defect in vitro and modest induction of endoplasmic reticulum (ER) stress. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD-associated kidney diseases and provides insights into the mechanisms of ADTKD and the genetic architecture of CKD.

Biosciences Institute Newcastle University Newcastle upon Tyne NE1 3BZ United Kingdom

Centre de Néphrologie et Transplantation Rénale Centre Hospitalier Universitaire Marseille 13005 France

Centre for Integrative Biological Signalling Studies University of Freiburg D 79106 Freiburg Germany

Department of Medicine Cantonal Hospital Frauenfeld 8501 Frauenfeld Switzerland

Department of Medicine Royal College of Surgeons in Ireland 1297 Dublin Ireland

Department of Nephrology and Hypertension Inselspital Bern University Hospital University of Bern 3010 Bern Switzerland

Department of Nephrology and Hypertension University Hospital Erlangen Friedrich Alexander Universität Erlangen Nürnberg 91054 Erlangen Germany

Department of Nephrology and Medical Intensive Care Charité Universitätsmedizin Berlin Freie Universität Berlin and Humboldt Universität zu Berlin 10117 Berlin Germany

Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University 128 08 Prague Czech Republic

Division of Nephrology Beaumont General Hospital 1297 Dublin Ireland

Division of Nephrology Cliniques Universitaires Saint Luc 1200 Brussels Belgium

Faculty of Biology University of Freiburg D 79106 Freiburg Germany

Genetics Department Laboratoire Eurofins Biomnis Lyon 69007 France

Institute of Genetic Epidemiology Faculty of Medicine and Medical Center University of Freiburg D 79106 Freiburg Germany

Institute of Physiology University of Zurich CH 8057 Zurich Switzerland

Marseille Medical Genetics Bioinformatics and Genetics Unité Mixte de Recherche _S910 Aix Marseille Université Marseille 13005 France

Molecular Genetics of Renal Disorders Division of Genetics and Cell Biology Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele Milan 20132 Italy

National Institute for Health and Care Research Newcastle Biomedical Research Centre Newcastle upon Tyne NE4 5PL United Kingdom

Renal Services Newcastle Upon Tyne Hospitals National Health Service Trust Newcastle upon Tyne NE7 7DN United Kingdom

Section on Nephrology Wake Forest School of Medicine Winston Salem NC 27101

Translational and Clinical Research Institute Newcastle University Newcastle upon Tyne NE1 3BZ United Kingdom

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Kidney Int. 2023 Feb;103(2):248-250. doi: 10.1016/j.kint.2022.11.018. PubMed

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Disrupted uromodulin trafficking is rescued by targeting TMED cargo receptors

Autosomal dominant tubulointerstitial kidney disease: A review