Ciliogenic pancreatopathy reveals a link between ciliopathies and exocrine pancreatic disease.

Abstract

While pancreatic cysts have been described in syndromic ciliopathies, the pancreas is not commonly recognised as a target organ. However, several ciliary gene knockout mouse models develop a pancreatic phenotype combining acinar atrophy and adipocyte accumulation, here called adipopancreatosis, suggesting a link between ciliary dysfunction and pancreatic disease. We investigated whether mutations in ciliopathy-associated genes are linked to pancreatic dysfunction in humans. We analysed a cohort of 341 patients with paediatric-onset pancreatic anomalies and characterised the pancreatic phenotype of new mouse models with conditional <i>Nphp3</i> inactivation or bearing <i>Nphp3</i> mutations recapitulating human mutations. In patients, pancreatic fat content was quantified using Dixon-MRI. Mutations in the cilium-related <i>HNF1B</i> and <i>NPHP3</i> were identified in patients presenting with both renal and pancreatic dysfunction. <i>Nphp3</i> mutant mice developed acinar atrophy, adipopancreatosis and moderate inflammation. Adipocytes in the pancreas exhibited a white adipocyte-like profile and may originate from mesothelial-derived fibroblasts. Reduced numbers and altered length of ductal cilia were monitored. Interestingly, secretory canaliculi, typically unnoticed structures found within and between acinar cells and connected to the acinar lumen, exhibited a microcystic morphology. Consistent with the mouse phenotype, Dixon-MRI revealed significantly increased pancreatic fat content in patients with <i>HNF1B</i> and <i>NPHP3</i> mutations. We describe a previously unrecognised pancreatic manifestation of ciliopathies, which we name ciliogenic pancreatopathy. Patients with known ciliopathy-causing mutations should be evaluated for this pancreatic condition, particularly those with kidney disease, as concomitant exocrine pancreatic insufficiency may further compromise renal function or the outcome of kidney graft.