Published: 24-02-2021 20:00 | Updated: 25-02-2021 09:00

Genetic cause of severe liver disease discovered

Illustration of liver surrounded by medical professionals.
Illustration: Getty Images.

Liver transplantation is currently the only treatment available for the severe liver disease PSC. Now, however, researchers at Karolinska Institutet and Oslo University have discovered the first reported genetic mutation that causes PSC. The study, which is published in Science Translational Medicine, opens new paths to future treatments.

Portrait of Niklas Björkström.
Niklas Björkström. Photo: Markus Marcetic.

Primary sclerosing cholangitis, or PSC, is a rare chronic inflammatory disease of the bile ducts. It normally debuts in young adults and two thirds of patients are men. In most cases, the patient also has an inflammatory bowel disease, such as ulcerative colitis or Crohn’s disease.

The patients run a high risk of bile duct cancer and/or cirrhosis of the liver, and today liver transplantation is the only available treatment. The cause of the disease is still unknown.

A family with PSC

Researchers at Karolinska Institutet and Oslo University have now described for what seems to be the first time a family with an autosomal dominant form of PSC, with five affected and 13 healthy family members. An autosomal dominant disease is an inherited disease that an individual can develop even if only one of the parents has the abnormal gene.

By analysing the DNA of the family members, the researchers found a genetic mutation in the five patients that was not found in their healthy kin.

“The mutation localises to a molecule that exists on the surface of many white blood cells, including immune system T cells,” says Niklas Björkström, doctor and researcher at the Center for Infectious Medicine, Karolinska Institutet (Huddinge) and one of the study’s senior authors.

Disrupted T cell function

The researchers re-created a genetic mutation in mice that was identical to that in the family members with PSC. The mice developed PSC-like symptoms, which suggests that the identified mutation actually caused the disease in the group under study.

Annika Bergquist. Photo: Stefan Zimmerman.

Finally, the researchers managed to show that the mutation also disrupted T cell function. When these cells were replaced with normal T cells, the mice bearing the mutation could return to health.

“This is a great step forward that helps us understand PSC,” says Annika Bergquist, adjunct professor at the Department of Medicine, Karolinska Institutet (Huddinge), consultant at Karolinska University Hospital’s gastroenterology unit and clinical researcher in charge of the study in Stockholm. “A treatment that stops the disease progressing is urgent, and a vital route to this end is learning more about the mechanisms behind this disease.”

First genetic explanation

Their findings contribute to a genetic explanation of PSC. Their focus now is on finding how the results can be used to develop new future treatments.

The study was financed by Helse Sør-Øst, the Jebsen Inflammation Research Centre (JIRC), the Norwegian PSC Centre, the Swedish Research Council, the Swedish Cancer Society, the Swedish Foundation for Strategic Research, the Swedish Society for Medical Research, the Cancer Research Funds of Radiumhemmet, the Knut and Alice Wallenberg Foundation, the Novo Nordisk Foundation, the Centre for Innovative Medicine, Region Stockholm and Karolinska Institutet. There are no reported conflicts of interest.


 “A heterozygous germline CD100 mutation in a family with primary sclerosing cholangitis”. Xiaojun Jiang, Annika Bergquist, Britt-Sabina Löscher, Geetha Venkatesh, Jeff E. Mold, Kristian Holm, Jon K. Laerdahl, Sigrid S. Skånland, Kimia T. Maleki, Martin Cornillet, Kjetil Taskén, Andre Franke, Tom Hemming Karlsen, Niklas K. Björkström*, Espen Melum*. Science Translational Medicine, online February 24 2021, doi: 10.1126/scitranslmed.abb0036. *Joint senior authors