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.

Center for Biomedical Network Research on Rare Diseases Madrid Spain

Department of Clinical and Biological Sciences University of Turin Turin Italy

Department of Internal Medicine Academic Teaching Hospital Feldkirch Feldkirch Austria

Department of Medical and Surgical Specialties Radiological Sciences and Public Health University of Brescia and Montichiari Hospital Brescia Italy

Department of Medicine Royal College of Surgeons in Ireland Dublin Ireland

Department of Nephrology and Gastroenterology Heim Pál Hospital for Children Budapest Hungary

Department of Nephrology and Renal Transplant of Centro Hospitalar Universitário Lisboa Norte EPE Lisbon Portugal

Department of Nephrology and Transplantation Istituto G Gaslini Istituto di Ricovero e Cura a Carattere Scientifico Genoa Italy

Department of Nephrology Klinikum rechts der Isar Technical University of Munich Munich Germany

Department of Renal Medicine University College London London UK

Division of Nephrology and Dialysis University of Brescia and Montichiari Hospital Brescia Italy

Division of Nephrology UCLouvain Medical School Brussels Belgium

Division of Nephrology Washington University in St Louis School of Medicine St Louis Missouri USA

Foundation for Biomedical Research of La Paz University Hospital IdiPaz Madrid Spain

GenoMed SA Instituto de Medicina Molecular Faculdade de Medicina Universidade de Lisboa Lisboa Portugal

Human Genetics and Genomic Medicine Faculty of Medicine University of Southhampton Southhampton UK

Medical Genetics Department of Medical Sciences University of Turin Turin Italy

Molecular Genetics of Renal Disorders Division of Genetics and Cell Biology Istituti di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute Milan Italy

Multi User Laboratory to Support Research in Nephrology and Medical Sciences Federal Fluminense University Niterói Rio de Janeiro Brazil

Nephrology Department Beaumont Hospital Dublin Ireland

Research Unit of Rare Diseases Department of Pediatric and Adolescent Medicine 1st Faculty of Medicine Charles University Prague Czech Republic

Section on Nephrology Wake Forest School of Medicine Winston Salem North Carolina USA

ToxOmics Centre for Toxicogenomics and Human Health NOVA Medical School New University of Lisbon Lisbon Portugal

University of Zurich Institute of Mechanisms of Inherited Kidney Disorders Zurich Switzerland

Wessex Kidney Centre Queen Alexandra Hospital Portsmouth Hospitals NHS Trust Portsmouth UK

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