Ciliogenic pancreatopathy reveals a link between ciliopathies and exocrine pancreatic disease

Background While pancreatic cysts have been described in syndromic ciliopathies, the pancreas is not commonly recognized as a target organ. However, several ciliary gene knockout mouse models develop a pancreatic phenotype combining acinar atrophy and adipocyte accumulation, hereby called adipopancreatosis, suggesting a link between ciliary dysfunction and pancreatic disease. Objective We investigated whether mutations in ciliopathy-associated genes are linked to pancreatic dysfunction in humans. Design We analyzed a cohort of 341 patients with pediatric-onset pancreatic anomalies and characterized the pancreatic phenotype of new mouse models with conditional Nphp3 inactivation or bearing Nphp3 mutations recapitulating human mutations. In patients, pancreatic fat content was quantified using Dixon-MRI. Results Mutations in the cilium-related HNF1B and NPHP3 were identified in patients presenting with both renal and pancreatic dysfunction. Nphp3 mutant mice developed acinar atrophy, adipopancreatosis, and moderate inflammation. Adipocytes in the pancreas exhibited a white adipocyte-like profile and likely originated 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 HNF1B and NPHP3 mutations. Conclusion We describe a previously unrecognized 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. What is already known on this topic Ciliopathies, resulting from defects in primary cilia, are genetic disorders primarily affecting the kidney and liver. Pancreatic cysts have been sporadically reported in syndromic ciliopathies. The pancreas is not currently recognized as a major target organ of ciliary dysfunction. A clear link between ciliary gene mutations and pancreatic anomalies is still unknown. Animal studies have suggested a possible association between ciliary dysfunction and pancreatic anomalies. What this study adds Identifies HNF1B and NPHP3 mutations as genetic causes of a pancreatic phenotype characterized by acinar atrophy and adipose replacement (adipopancreatosis). Demonstrates the presence of defective ductal cilia and moderate inflammation in the pancreas of Nphp3 mutant mice. Reveals that secretory canaliculi in the exocrine pancreas of Nphp3 mutant mice acquire a microcystic morphology. Shows that patients with HNF1B or NPHP3 mutations have significantly increased pancreatic fat content by Dixon-MRI. Defines a new disease entity, ciliogenic pancreatopathy, as a pancreatic manifestation of ciliopathies. How this study might affect research, practice or policy Establishes the pancreas as a novel and clinically relevant target of ciliopathies. Expands the phenotypic spectrum of HNF1B- and NPHP3-related diseases to include exocrine pancreatic dysfunction. Suggests that patients with ciliopathy-causing mutations should be evaluated for exocrine pancreatic insufficiency. Highlights the need to consider pancreatic function monitoring in kidney disease and transplant settings. Opens new research avenues into the role of primary cilia in pancreatic homeostasis and disease.