Submission Details

Dedicator of cytokinesis 2 (DOCK2) was first predicted in Nagase et al in 1996 (PMID 9039502) and was first reported by Nishihara et al. in 1999 (PMID10559471) as a member of the CDM family of proteins. Variants in DOCK2 were first reported in patients in 2015 (Dobbs K, et al., 2015, PMID: 26083206). DOCK2 is a major guanine nucleotide-exchange factor (GEF) for GTPase-activating proteins, and is primarily expressed in hematopoietic cells (PMID: 10559471). It binds and activates Rac through its DOCK homology region domain, and subsequently activated Rac serves multiple functions downstream of G protein-coupled receptors (GPCR) and antigen and complement receptors, including reorganization of the actin cytoskeleton (PMID: 11518968). Sixteen variants, (including frameshift, nonsense, splice altering, and missense) have been reported in 8 probands in 4 publications (PMIDs: 26083206, 29204803, 30838481, 30826364). Affected individuals typically present early-onset invasive viral and bacterial infections, naïve T cell lymphopenia with reduced T cell receptor excision circles (TRECs) and diminished T cell proliferation in response to phytohemagglutinin, variable reduction of B cell numbers, with defective antibody responses despite normal immunoglobulin G levels, and impaired NK cell function. Total polymerized filamentous actin was diminished in T-, B-, and NK lymphocytes, and T- and B cell chemotaxis was also impaired by DOCK2 deficiency (PMID: 26083206). Interferon (IFN)-alpha and -lambda production by peripheral blood mononuclear cells from DOCK2-deficient patients was reduced after ex vivo exposure to herpes simplex virus 1 or vesicular stomatitis virus. Moreover, DOCK2 deficient simian virus 40 fibroblasts showed increased viral replication and enhanced virus-induced cell death after exposure to encephalomyocarditis virus. Both treatment with recombinant IFN-α2b and lentiviral-mediated wild-type DOCK2 expression protected DOCK2-deficient fibroblasts from virus-induced cell death. The DOCK2 mutations may therefore also impair cell-intrinsic, non-hematopoietic immunity, at least in fibroblasts and in response to some viruses (PMID: 26083206). As in humans, DOCK2-deficient mice (DOCK2-/-) exhibited migration defects of T and B lymphocytes, but not of monocytes, in response to chemokines, resulting in several abnormalities including T lymphocytopenia, atrophy of lymphoid follicles and loss of marginal-zone B cells. In DOCK2-/- lymphocytes, chemokine-induced Rac activation and actin polymerization were almost totally abolished (PMID: 11518968). In summary, DOCK2 is definitively associated with autosomal recessive DOCK2 deficiency. This has been repeatedly demonstrated in both the research and the clinical diagnostic setting and has been upheld over time. Classification approved by SCID-CID GCEP on ___.