Abstract: Objectives In the study, we screened genetic variations in UMOD, REN and HNF1B genes in a Chinese autosomal dominant tubulointerstitial kidney disease (ADTKD) cohort and studied the pathogenesis of ADTKD with novel UMOD mutations. Methods Forty-four probands from 44 different families were recruited
according to the KDIGO report of diagnostic criteria for suspected ADTKD. We sequenced all exons of the three genes and used multiple ligation-dependent probe amplification (MLPA) assays for copy number variations in HNF1B. We then detected uromodulin expression after transfection of the mutant UMOD cDNA
plasmid into HEK293 (human embryonic kidney) cells. Results We detected 11 mutations (10 in UMOD, 1 in HNF1B) in this cohort, and 3 of them (c.104G>A, c.113A＞T and c.860G>T) were novel mutations in UMOD. Point mutations in REN and copy number variations in HNF1B were not found. We divided the 44
probands into two groups according to the presence and absence of UMOD mutation and found no distinct discrimination in clinical characteristics between the two groups. Uromodulin expression were significantly decreased in HKE293 cells after transfected with the mutant plasmid (F=14.241, P＜0.001), consistent with the previous research results. Conclusions About 25% of patients in our ADTKD cohort were found to have mutations in UMOD gene. Clinical features were nonspecific in patients with UMOD mutations. These results indicate that gene sequencing is one of the important methods for the diagnosis of ADTKD.

Key words: Autosomal dominant tubulointerstitial kidney disease, UMOD, HNF1β, REN, Mutation screening