Ciliogenic pancreatopathy reveals a link between ciliopathies and exocrine pancreatic disease

Background Ciliopathies are genetic disorders affecting primary cilia, most commonly affecting the kidney and liver. Although 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 characterized by acinar atrophy and adipocyte accumulation, hereby called adipopancreatosis, suggesting a link between ciliary dysfunction and pancreatic disease. Objective To investigate whether mutations in ciliopathy-associated genes are associated with pancreatic dysfunction in humans, and to explore the underlying mechanisms. Design We analyzed a cohort of 341 patients with pediatric-onset pancreatic anomalies. In parallel, we generated Nphp3 patient-specific and conditional knockout mouse models to characterize pancreatic alterations at histological, molecular, and cellular levels. In patients, pancreatic fat content was quantified using Dixon-MRI. Results Mutations in HNF1B and NPHP3 were identified in patients presenting both renal ciliopathy and pancreatic dysfunction. Nphp3 mutant and conditional knockout mice developed progressive adipopancreatosis with acinar atrophy and distinct inflammatory profiles. Transcriptomic analyses indicated that the adipocytes displayed a white adipocyte–like gene expression profile and mesothelial-derived fibroblasts were implicated as a likely cellular origin. Additional pathological features included ductal cilium alterations and acinar microcysts. Consistent with the mouse phenotype, Dixon-MRI in patients with HNF1B and NPHP3 mutations demonstrated significantly increased pancreatic fat content. Conclusion We describe a previously unrecognized pancreatic manifestation of ciliopathies, which we term ciliogenic pancreatopathy. Our findings suggest that patients with known ciliopathy-associated mutations should be evaluated for this pancreatic condition during clinical assessments, particularly those with kidney disease, as concomitant exocrine pancreatic insufficiency may further compromise renal function or the outcome of kidney graft.