Discovery of DOCK11 mutations responsible for a new X-linked autoimmune disease

How a defect in the cellular skeleton leads to a deregulation of the immune response :
In a new study published in the journal Blood, researchers from the "Immunogenetics of Pediatric Autoimmune Diseases" team at Institut Imagine (Inserm, APHP, Université Paris Cité) in collaboration with the Université Paris-Saclay, have demonstrated the impact of mutations in the DOCK11 gene on lymphocyte morphology and size as a result of a defect in the remodelling of their cytoskeleton (the molecular skeleton of the cells). These mutations have been found in children with various and sometimes severe autoimmune manifestations.

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By taking advantage of the March 2020 lockdown period to analyse the DNA sequencing of patients suffering from early autoimmune diseases, Laure Delage, from Frédéric Rieux-Laucat's team, has identified the first variants of the DOCK11 gene in several children. These diseases are manifested by attacks by the immune system on platelets or red blood cells, the skin or the intestine. Mutations in the DOCK (Dedicator of cytokinesis) family of genes, DOCK2 and DOCK8, associated with severe viral infections, were already known to play a central role in the regulation of the actin cytoskeleton, an evolutionary structure that enables cell deformation and migration. A similar role for DOCK11 was previously suspected, but very few studies had been published on its function.

In their work published in the journal Blood [1], Dr Rieux-Laucat's team describes for the first time the association of DOCK11 mutations with autoimmune diseases observed in young boys. After the discovery of these mutations, Charlotte Boussard began to study the morphological and functional characteristics of patients' platelets, in collaboration with Frédéric Adam's team, from the UMR S1176 at Kremlin-Bicêtre. The scientists were able to observe a 'pre-activation' state of the platelets, with reduced activity of CDC42, a protein central to the remodelling of the actin cytoskeleton. These observations confirmed the causal role of DOCK11 mutations.

In collaboration with the team of Dr Fernando Sepulveda, co-director of the "Molecular bases of immune homeostasis anomalies" laboratory at Institut Imagine, the researchers measured the speed of migration through microchannels of certain immune cells (T and B lymphocytes) carrying these mutations. The result: the speed of migration is increased, reflecting abnormal remodelling of the actin cytoskeleton. In parallel, Charlotte Boussard and Laure Delage observed these immune cells using electron and confocal microscopy and showed an abnormal cell architecture (see photo) compared to lymphocytes from healthy donors.

La cellule mutée présente une forme anormale (contrôle à droite)
La cellule mutée présente une forme anormale (contrôle à droite)

When studying regulatory T cells, the cells that prevent the development of an autoimmune response, the team also detected an abnormally low level of the transcription factor FOXP3. This protein, known to be affected in other early and severe autoimmune diseases, is essential for the protective function of these regulatory lymphocytes. This observation could be the consequence of a defect in the response to interleukin-2, a lymphocyte growth factor, on which regulatory T cells are particularly dependent.

Taken together, these results demonstrated the causal role of DOCK11 mutations in cell morphology abnormalities and immune dysregulation leading to the early onset of autoimmune diseases. Symptoms due to DOCK11 mutations have only been observed in young boys, as the gene is carried on the X chromosome. To date, more than 15 mutations have been characterised at Institut Imagine; as this pioneering work describes a new cause of autoimmune disease, the Institute's partner centres will now be able to diagnose the disease in turn. Thanks to the joint efforts of clinicians and researchers, and the willingness of families, a new field of investigation for autoimmune diseases has opened up for the benefit of children followed at the Institute and throughout the world.


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