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.J.A.S. is supported by the Kidney Research Fund and the Medical Research Council (MR/M012212/1). S.A.R. is a Kidney Research UK Post-Doctoral Fellow. O.D. is supported by grants from the European Community’s Seventh Framework Programme (305608 EURenOmics), the Swiss National Centre of Competence in Research Kidney Control of Homeostasis (NCCR Kidney.CH) programme, the Swiss National Science Foundation (31003A_169850) and the Rare Disease Initiative Zu¨rich (Radiz), a clinical research priority program of the University of Zurich, Switzerland. E.O. is supported by the Fonds National de la Recherche Luxembourg (6903109) and the University Research Priority Programme ‘Integrative Human Physiology, ZIHP’ of the University of Zurich
