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Journal Articles Blood Year : 2023

DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity

Tania Gajardo
  • Function : Author
Alexandre Kauskot
  • Function : Author
Maxime Batignes
  • Function : Author
Nicolas Goudin
  • Function : Author
Marie-Claude Stolzenberg
  • Function : Author
Camille Brunaud
  • Function : Author
Patricia Panikulam
  • Function : Author
Quentin Riller
  • Function : Author
Maryse Moya-Nilges
  • Function : Author
Jean Solarz
  • Function : Author
Christelle Repérant
  • Function : Author
Béatrice Durel
  • Function : Author
Jean-Claude Bordet
  • Function : Author
Olivier Pellé
  • Function : Author
Corinne Lebreton
  • Function : Author
Aude Magérus
  • Function : Author
Vithura Pirabakaran
  • Function : Author
Pablo Vargas
  • Function : Author
Sébastien Dupichaud
  • Function : Author
Marie Jeanpierre
  • Function : Author
Mohammed Zarhrate
  • Function : Author
Cécile Masson
  • Function : Author
Nathalie Aladjidi
  • Function : Author
Peter D. Arkwright
  • Function : Author
Brigitte Bader-Meunier
Sandrine Baron Joly
  • Function : Author
Joy Benadiba
  • Function : Author
Elise Bernard
  • Function : Author
Dominique Berrebi
  • Function : Author
Christine Bodemer
Martin Castelle
  • Function : Author
Fabienne Charbit-Henrion
  • Function : Author
Marwa Chbihi
  • Function : Author
Philippe Drabent
  • Function : Author
Sylvie Fraitag
  • Function : Author
Ludovic Lhermitte
  • Function : Author
Despina Moshous
  • Function : Author
Pierre Rohrlich
  • Function : Author
Frank Ruemmele
  • Function : Author
Anne Welfringer-Morin
  • Function : Author
Maud Tusseau
  • Function : Author
Alexandre Belot
  • Function : Author
Nadine Cerf-Bensussan
  • Function : Author
Marie Roelens
  • Function : Author
Capucine Picard
  • Function : Author
Bénédicte Neven
  • Function : Author
Alain Fischer
  • Function : Author
Mickaël Ménager
  • Function : Author
Fernando E. Sepulveda
  • Function : Author
Frédéric Adam
  • Function : Author

Abstract

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.
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Dates and versions

hal-04246983 , version 1 (18-10-2023)

Identifiers

  • HAL Id : hal-04246983 , version 1

Cite

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⟩
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