DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity

Charlotte Boussard (1) , Laure Delage (1) , Tania Gajardo , Alexandre Kauskot , Maxime Batignes , Nicolas Goudin , Marie-Claude Stolzenberg , Camille Brunaud , Patricia Panikulam , Quentin Riller , Maryse Moya-Nilges , Jean Solarz , Christelle Repérant , Béatrice Durel , Jean-Claude Bordet , Olivier Pellé , Corinne Lebreton , Aude Magérus , Vithura Pirabakaran , Pablo Vargas , Sébastien Dupichaud , Marie Jeanpierre , Angélique Vinit (2, 3) , Mohammed Zarhrate , Cécile Masson , Nathalie Aladjidi , Peter D. Arkwright , Brigitte Bader-Meunier , Sandrine Baron Joly , Joy Benadiba , Elise Bernard , Dominique Berrebi , Christine Bodemer , Martin Castelle , Fabienne Charbit-Henrion , Marwa Chbihi , Agathe Debray (4) , Philippe Drabent , Sylvie Fraitag , Miguel Hié (5) , Judith Landmann-Parker (4) , Ludovic Lhermitte , Despina Moshous , Pierre Rohrlich , Frank Ruemmele , Anne Welfringer-Morin , Maud Tusseau , Alexandre Belot , Nadine Cerf-Bensussan , Marie Roelens , Capucine Picard , Bénédicte Neven , Alain Fischer , Isabelle Callebaut (6) , Mickaël Ménager , Fernando E. Sepulveda , Frédéric Adam , Frédéric Rieux-Laucat (1)

1 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
2 PASS-CYPS - Cytométrie Pitié-Salpêtrière
3 PASS - Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé
4 CHU Trousseau [APHP]
5 CIMI - Centre d'Immunologie et des Maladies Infectieuses
6 IMPMC - Institut de minéralogie, de physique des matériaux et de cosmochimie

Dedicator of cytokinesis (DOCK) proteins play a central role in actin cytoskeleton regulation. This is highlighted by the DOCK2 and DOCK8 deficiencies leading to actinopathies and immune deficiencies. DOCK8 and DOCK11 activate CDC42, a RHO-GTPase involved in actin cytoskeleton dynamics, among many cellular functions. The role of DOCK11 in human immune disease has been long suspected but has never been described so far. We studied eight male patients, from seven unrelated families, with hemizygous DOCK11 missense variants leading to reduced DOCK11 expression. The patients were presenting with early-onset autoimmunity, including cytopenia, systemic lupus erythematosus, skin, and digestive manifestations. Patients’ platelets exhibited abnormal ultrastructural morphology and spreading as well as impaired CDC42 activity. In vitro activated T cells and B lymphoblastoid cell lines (B-LCL) of patients exhibited aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. A DOCK11 knock-down recapitulated these abnormal cellular phenotypes in monocytes-derived dendritic cells (MDDC) and primary activated T cells from healthy controls. Lastly, in line with the patients’ autoimmune manifestations, we also observed abnormal regulatory T cells (Tregs) phenotype with profoundly reduced FOXP3 and IKZF2 expression. Moreover, we found a reduced T cell proliferation and an impaired STAT5B phosphorylation upon IL2 stimulation of the patients’ lymphocytes. In conclusion, DOCK11 deficiency is a new X-linked immune-related actinopathy leading to impaired CDC42 activity and STAT5 activation, and associated with abnormal actin cytoskeleton remodeling as well as Tregs phenotype culminating in immune dysregulation and severe early-onset autoimmunity.

Domaines: Sciences du Vivant [q-bio]

Charlotte Boussard, Laure Delage, Tania Gajardo, Alexandre Kauskot, Maxime Batignes, et al.. DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity. Blood, 2023. ⟨hal-04246983⟩