A new pancreatic disease linked to ciliopathies

Ciliopathies are rare genetic disorders caused by defects in primary cilia, structures that play essential roles in cell signaling and organ development. They are best known for affecting organs such as the kidneys and liver, while the pancreas has not traditionally been considered a major target of ciliary dysfunction. This study, conducted by Patrick Jacquemin, group leader at the de Duve Institute, and Isabelle Scheers, pediatric gastroenterologist at the Cliniques universitaires Saint-Luc and clinical researcher at the de Duve Institute, identifies a previously unrecognized pancreatic manifestation of ciliopathies, termed ciliogenic pancreatopathy by the authors. This condition is characterized by the progressive loss of pancreatic acinar tissue and its replacement by adipose tissue, a process they call adipopancreatosis.

The researchers investigated a cohort of 341 patients with pediatric-onset pancreatic abnormalities and identified mutations in the ciliary genes HNF1B and NPHP3 in patients presenting with both pancreatic and kidney abnormalities.

To understand the mechanisms underlying this pancreatic phenotype, Memoona Rajput, co-first author of the study, developed and analyzed new mouse models carrying patient-derived Nphp3 mutations or a conditional deletion of Nphp3 specifically in pancreatic ductal cells. These models displayed progressive acinar atrophy and adipopancreatosis. The study also revealed several previously unrecognized structural abnormalities in the pancreas of Nphp3 mutant mice. Similar abnormalities were observed in other mouse models of ciliary dysfunction, suggesting that they may represent a common feature of ciliogenic pancreatic disease.

The researchers further found that the adipocytes accumulating in the pancreas displayed a molecular profile similar to that of white adipocytes and may arise from resident mesothelial-derived fibroblasts. Based on these findings in mouse models, the researchers then investigated whether a similar pancreatic phenotype could be detected in patients carrying HNF1B or NPHP3 mutations. Using non-invasive Dixon-MRI, they measured pancreatic fat content in patients and matched healthy controls. They found significantly higher pancreatic fat content in patients with HNF1B or NPHP3 mutations, supporting the presence of adipopancreatosis in these patients and providing evidence that the pancreatic phenotype identified in mice also occurs in humans.

Together, these results establish the pancreas as a clinically relevant target of ciliopathies and expand the known spectrum of HNF1B- and NPHP3-related diseases to include exocrine pancreatic dysfunction. These findings have important clinical implications. Patients carrying mutations in HNF1B, NPHP3, and potentially other ciliopathy-associated genes may benefit from evaluation of pancreatic structure and exocrine function, particularly when unexplained gastrointestinal symptoms are present. Early detection may be particularly important in patients with kidney disease, as exocrine pancreatic insufficiency can lead to nutritional complications and may further compromise renal function through increased intestinal oxalate absorption. Further studies will be needed to determine how frequent ciliogenic pancreatopathy is across different ciliopathies and whether early intervention or therapies targeting ciliary function could prevent or reverse pancreatic damage.

Picture showing two cells (in the box) with a primary cilium (red), where the NPHP3 protein can be detected (green)

Article describing this research

Ciliogenic pancreatopathy reveals a link between ciliopathies and exocrine pancreatic disease

Rajput M, Flasse L, Porée E, Pointeau O, Serafin A, Papadopoulos N, Achouri Y, Moro J, Loriot A, Wilsch-Brauninger M, Gillion V, Godefroid N, Bodson C, Lopez Muneta L, Depestel C, Morel M, Cordi S, Garcia de Herreros A, Haumaitre C, Lemaigre F, Rovira M, Viau A, Grapin-Botton A, Saunier S, Jacquemin P, Scheers I

Gut (2026) gutjnl-2025-337224