Human DOCK11 deficiency: a new X-linked actinopathy associated with early onset auto-immunity

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Abstract

Background:
DOCK11 (Dedicator Of Cytokinesis 11) is a guanine nucleotide exchange factor (GEF), part of the DOCK protein family. Predominantly expressed in hematopoietic cells, DOCK11 binds and activates CDC42, a RAS-related GTP-binding protein involved in actin regulation. The description of DOCK2 and DOCK8 immune-related actinopathies highlighted the role of the DOCK protein family in the immune system. A role of DOCK11 in human immune disease has been long suspected but never been described so far.

Methods:
Eight patients with early onset auto-immunity from seven unrelated were studied. We performed exome analysis and confirmed variant with targeted Sanger sequencing. X-linked DOCK11 variants were predicted deleterious. We evaluated CDC42 activity in patient platelets and their platelet functions. We studied actin cytoskeleton rearrangements of platelets, activated T cells and B lymphoblastoid cell lines (B-LCL). We performed knockdown DOCK11 model on monocytes-derived dendritic cells to evaluate DOCK11 pathological function.

Results:
We identified hemizygous missense mutations of DOCK11 gene in patients with early onset auto-immunity including cytopenia, SLE, skin and digestive manifestations. Patients presented a reduced DOCK11 protein expression in their activated T cells and platelets. CDC42 activity was impaired in patient platelets upon activation. Platelet and T cell spreading were abnormal. Patient activated T cells have increased migration speed in confined channels concomitant with
impaired polarization of actin polymerization. MDDc with DOCK11 knockdown had aberrant podosomes.

Conclusions:
DOCK11 deficiency is a new X-linked immune actinopathy leading to abnormal actin cytoskeleton remodeling, with impaired CDC42 activity and immune dysregulation.
Original languageEnglish
JournalBlood
Publication statusAccepted/In press - 20 Mar 2023

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