A team led by LMU physician Daniel Kotlarz has identified a previously unknown genetic cause of Crohn's disease.

Chronic inflammatory bowel diseases are increasing worldwide. Despite major advances in diagnostics and therapy, the underlying causes of these diseases often remain poorly understood. An international research team from the VEO-IBD Consortium (a global research network supported by The Leona M. and Harry B. Helmsley Charitable Trust), involving LMU University Hospital and The Hospital for Sick Children (SickKids) in Toronto has identified a previously unknown genetic cause of chronic inflammatory bowel diseases. The results were published in the journal Gastroenterology.

Researchers from Canada, Germany, the United States, China, Japan, France, Spain, and Saudi Arabia took part in the study. “The work highlights the importance of international collaborations for elucidating rare diseases and developing new therapeutic approaches for chronic inflammatory bowel diseases,” says Daniel Kotlarz, Heisenberg Professor for Precision Medicine of Pediatric IBD at LMU University Hospital and one of the corresponding authors of the study.

The researchers showed that pathogenic variants in the gene BIRC3 can cause a severe form of Crohn’s disease. During the study, they identified 14 patients from 10 different families carrying pathogenic variants in BIRC3. Using state-of-the-art genetic, transcriptomic, and proteomic analyses and experimental model systems, the researchers managed to elucidate the underlying disease mechanisms.

The study shows that loss of BIRC3 function leads to dysregulation of the RIPK1 signaling pathway in the intestinal epithelium. “Our results demonstrate for the first time how loss of BIRC3 impairs the protective function of the intestinal mucosa in patients and thus promotes chronic inflammations,” says Xiang Shen, shared first author of the study and scientist at the Dr. von Hauner Children’s Hospital at LMU University Hospital.

The importance of the findings extends beyond rare genetic diseases. The researchers found indications that the same signaling pathway could also play an important role in more common forms of Crohn’s disease. “This study impressively demonstrates the added value that international research networks bring to the understanding of rare diseases.

It was only through close collaboration among clinicians and researchers worldwide that we were able to identify enough affected individuals to uncover a new disease mechanism and a potential therapeutic target,” explains Dr. Aleixo Muise, a senior scientist at SickKids and co-director of the IBD Center, one of the leaders of the international study.

For the researchers, the study is an important step on the path to precision medicine for chronic inflammatory bowel diseases. “Rare monogenetic diseases permit unique insights into the biological causes of chronic inflammatory bowel diseases,” says Daniel Kotlarz. “The discovery of BIRC3 deficiency not only furnishes a new diagnosis for affected families, but opens up potential new approaches for targeted therapies, from which larger patient groups could also benefit in the future.”