Dedicator of cytokinesis 8 (DOCK8) deficiency.
OBJECTIVE
To describe a new combined primary immunodeficiency disease, previously known as autosomal recessive hyper-IgE syndrome, whose molecular basis was discovered in 2009.


RESULTS
Two groups identified homozygous and compound heterozygous loss-of-function mutations in the Dedicator of cytokinesis 8 (DOCK8) gene in at least 30 patients who had been previously diagnosed with an atypical form of hyper-IgE syndrome. Absence of DOCK8 expression impairs T cell expansion in vitro, which could help explain the T cell lymphopenia and susceptibility to cutaneous viral infections observed in these patients. In mouse models of DOCK8 deficiency, absence of DOCK8 expression also impairs the generation of a durable secondary antibody response to specific antigens, which could account for the functional antibody abnormalities and recurrent sinopulmonary infections observed in the patients. Two patients have been cured of infectious complications after myeloablative allogeneic hematopoietic cell transplantation.


CONCLUSIONS
The discovery of the molecular basis of this disease is expected to facilitate diagnosis and definitive treatment with hematopoietic cell transplantation. Further research is needed to understand how DOCK8 normally functions in lymphocytes and how DOCK8 deficiency leads to disease.
Su
Helen C
HC
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. hsu@niaid.nih.gov
D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000276:immunology*; D006801:Humans; D056724:Immunity, Humoral / Q000235:genetics; D007239:Infections; D007589:Job Syndrome / Q000235:genetics* / Q000276:immunology* / Q000503:physiopathology; D008231:Lymphopenia; D051379:Mice; D009154:Mutation / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology*
C516591:DOCK8 protein, human; D020662:Guanine Nucleotide Exchange Factors