Loss of ADAMTS9 disrupts ciliogenesis and collagen homeostasis resulting in Nephronophthisis-like polycystic kidneys

<i>ADAMTS9</i> mutations cause the ciliopathies nephronophthisis and Joubert syndrome. Here we show that deletion of ADAMTS9 in the proximal nephron leads to polycystic kidney development in mice. In males, <i>Adamts9</i> deletion cause kidneys to become highly cystic but remain small without undergoing enlargement, causing early postnatal lethality. Female mice on the other hand, develop cystic kidneys but progress slowly. ADAMTS9 deletion disrupted ciliogenesis by the loss of ciliary transition zone (TZ) protein TMEM67 cleavage, leading to loss of the MKS/B9 module - a key component of the ciliary gate. Functional analysis of all eight ciliopathy patient variants of <i>ADAMTS9</i> identified to date, showed TMEM67 C-terminus failed to localize to the transition zone, thus disrupting a key regulatory mechanism in patient renal ciliogenesis. Modeling ADAMTS9-mediated TMEM67 cleavage utilizing our novel TMEM67-cleavage deficient mice revealed loss of TZ formation but not elevated canonical Wnt signaling as the underlying mechanism driving cystogenesis. We show that <i>Adamts9</i> deletion leads to comparatively intense interstitial collagen deposition, which likely restricts kidney enlargement resulting in the characteristically small kidney phenotype in nephronophthisis and increased immune response. By comparative analysis of four interconnected polycystic kidney models in addition to <i>Pkd1</i> and <i>Pkd2</i> deleted kidneys, we identify differential collagen homeostasis is the principle determining factor deciphering cystic kidney size and type.