How research on rare diseases can help understand the bigger picture: Example hemophagocytic syndrome

Researchers identified a new genetic cause of the rare hemophagocytic syndrome, a disease which is characterized by a dangerous and uncontrolled activation of the immune system. The discovery could inspire new treatments and provides new insights into the human immune system. The research was conducted in an international collaboration of VIB-UGent Center for Inflammation Research, Ghent University hospital, the Helmholtz Zentrum München and the National University of Australia in Canberra.

The displayed T cells reveal the localization of Roquin-1 proteins to Rck-positive RNA-Processing bodies (white arrows). The wildtype protein colocalizes with Rck (upper row), while the mutated version of Roquin-1 from the patient, is less active and does not accumulate in Processing bodies (lower row).

Hemophagocytic syndrome is a rare but deadly immune disease. It is estimated to afflict 1 in 100.000 children. In a number of children, genetic mutations have been identified that cause this overactivation. These mutations prevent the natural brakes of the human immune system from working. This means that the immune system keeps on fighting, even when the infection has already been resolved. Early recognition of the genetic mutations causing this fatal disease is crucial for any reasonable attempt to permanently restore a normal function of the immune system.

Exploring a rare case

Genetic analysis performed by researchers in Ghent identified a new mutation located in the Roquin-1 encoding gene in a young patient suffering from recurring hyperinflammation, resembling hemophagocytic syndrome. The international team of researchers then joined forces to explore the role of Roquin-1 in connection to hemophagocytic syndrome and in the human immune system in general.

In order to get there, researchers at Helmholtz Zentrum in München utilized a genetic mouse model, in which they were able to replace the mouse Roquin-1 protein in T cells with the one harboring the mutation found in the patient. Surprisingly, they found that the mutation only partially inactivated the gene regulation exerted by the Roquin-1 protein, causing increased expression of a number of target genes among them many cytokines but not others. This helped to understand the development of hemophagocytic syndrome.

New insights in the origins of immune diseases

On the one hand, the identification of this new mutation might help to diagnose hemophagocytic syndrome earlier and start a more suitable treatment. On the other hand, by identifying the role of Roquin-1 as a regulator of the human immune system, the researchers discovered a new mechanism how human immune diseases can arise.

Prof. Dr. Vigo Heissmeyer, leader of the research unit Molecular Immune Regulation at Helmholtz Zentrum München emphasizes the importance of these findings: “Our research will stimulate the scientific efforts to understand how Roquin-1 functions in the human immune system. It is likely that we will also find additional mutations in Roquin-1 in patients with other immune diseases such as autoimmunity.”


Original publication:
Tavernier et al., 2019: A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation. Nature Communications, DOI: 10.1038/s41467-019-12704-6

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