Currently, there are an estimated 10,000 known rare diseases (and counting). As we learn more about our genetic makeup, and how genetic alterations can cause disease, we continue to deepen our understanding and identify novel conditions. Inside Precision Medicine shared that research performed by the St. Anna Children’s Cancer Research Institute in Austria recently uncovered a novel genetic disease caused by rare, X-linked DOCK11 gene mutations. The research suggests that this previously unidentified condition is an inborn error of hematopoiesis (blood cell production) and immunity.
Identifying DOCK11 as Potentially Pathogenic
The researchers were alerted to a potential disease after four children came to the hospital with matching symptoms. Perhaps most interestingly, the children all had severe organ inflammation. It seemed widespread throughout the body with multiple affected systems, including the kidneys and skin. They also had infections, normocytic anemia, and developmental delays. To identify a potential cause, the researchers ran genetic, molecular, and immunologic testing on the children, as well as functional assays in murine, zebrafish, and patient-derived cellular models.
At first, the research team hypothesized that the children had an autoimmune disease. But the tests for autoimmune diseases came back negative. Later, shares a research article in the New England Journal of Medicine, DOCK11 gene mutations were found in all four patients.
What Does This Gene Do?
DOCK11, or dedicator of cytokinesis-11, is a protein-coding gene that normally plays a role in cytoskeleton organization. However, in these affected individuals, the hemizygous loss-of-function genetic mutations instead cause issues with blood cell formation and function. To test this, the researchers deactivated DOCK11 in zebrafish models. They found that when this gene was impaired, so was the development of healthy red blood cells. Further, shares the research:
In addition, the patient-derived T cells, as well as the T cells from Dock11-knockout mice, showed overt activation and production of proinflammatory cytokines that were associated with an increased degree of nuclear translocation of nuclear factor of activated T cell 1 (NFATc1).
Cytokine overproduction could contribute to the significant inflammation researchers noted at the onset of the study. Ultimately, there is still much that we don’t know about DOCK11 mutations – or even how these mutations drive disease. More research is needed to understand the role of DOCK11 in this novel condition and whether treatment could be developed.
