Autosomal dominant polycystic kidney disease (ADPKD) is characterized by slow progression of multiple cysts in both kidneys that lead to renal insufficiency in mid-life or later. ADPKD is associated with mutations mainly in the PKD1 gene (encoding polycystin-1 or PC1) and less frequently in the PKD2 gene (encoding polycystin-2 or PC2). To mimic naturally occurring human PKD1 mutations and gain insight into the PC1 extracellular domain function, four transgenic mouse lines were established with exclusively the extracellular domain of the Pkd1 gene (Pkd1(extra)) under endogenous transcriptional regulation. Expression of the Pkd1(extra) transgene was 2- to 80-fold above endogenous levels. Strikingly, the Pc1(extra) protein was more abundant, proportionally to the endogenous levels. All four transgenic mouse lines consistently displayed progressive renal cystic phenotype. Consequently, these transgenic mice reproducibly developed renal functional alterations similar to human ADPKD with proteinuria, renal insufficiency, anemia and died of renal failure late in life. In precystic kidneys, the Pkd1(extra) transgene modulated Pc2 expression and thereby, uncovered a potential Pc1-mutant/Pc2 pathogenic crosstalk mechanism. Moreover, the pathophysiologic mechanism also implicates c-myc, a major modulator of cystogenesis. Altogether, the novel Pkd1(extra) mouse model is the first Pc1 extracellular mutant that reproduces human ADPKD clinical progression and physiopathology.