Functional analyses of mutations in transcription factors associated to chronic pancreatitis

• Applicant: Professor Dr. Heiko Witt
• Subject Area: Pediatric and Adolescent Medicine
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 468167296

Chronic pancreatitis (CP) is an inflammatory disease of the pancreas characterized by recurrent agonizing pain, irreversible morphological changes, and impairment of exocrine and endocrine pancreatic function. As a consequence, patients develop maldigestion, steatorrhea and diabetes mellitus. The most serious complication in patients with long-lasting CP, however, is the development of pancreatic cancer.So far, genetic defects in eleven genes or genetic loci, respectively, associated to CP have been identified. All known susceptibility genes to date account for only 50% of hereditability in our paediatric cohort. Thus, several further disease causing genes have to exist. To identify these genes, we performed whole exome sequencing (WES) in a German discovery cohort of 550 CP patients and in a European replication cohort of 600 CP patients.Besides known susceptibility genes, we found several potential CP risk genes, three of them represent (pancreatic) transcription factors. We hypothesize that variants identified by WES in the genes encoding RBPJL, HNF1A and NR5A2 impair protein-DNA binding capacity, protein-protein interaction of transcription factor complexes, nuclear localization or transcriptional activity, and thus finally endogenous target gene expression. In this project, we will characterize the functional effects of the mutations found in detail.Given the importance of all three transcription factors for pancreatic cell identity, integrity and regulation of numerous acinar cell specific genes, these mutations might have a huge impact on pancreas homeostasis. Besides contributing to in-depth uncovering genetic heritability of pancreatitis, our results may additionally guide further understanding of the precise pathological conditions of pancreatitis and even pancreatic cancer.

• DFG Programme: Research Grants