DOCK8 Gene

The DOCK8 gene (DOCK8 stands for Dedicator Of Cytokinesis 8) is a protein coding gene located on chromosome 9p24.3. The protein encoded by the DOCK8 gene, is a member of the DOCK180 family of guanine nucleotide exchange factors. Guanine nucleotide exchange factors interact with Rho GTPases and are components of intracellular signaling networks. Alternatively spliced transcript variants encoding different isoforms have been described.

The guanine nucleotide exchange factor (GEF) encoded by the DOCK8 gene specifically activates the small GTPase CDC42 by exchanging bound GDP for free GTP. GEF is required in immune responses, namely for interstitial migration of dendritic cells (DC) by local activation of the small GTPase CDC42 placed at the T cell leading edge. Furthermore, guanine nucleotide exchange factor is involved in NK cell cytotoxicity by controlling microtubule organizing center (MTOC) polarization and possibly regulating CCDC88B-mediated lytic granule transport to MTOC during cell killing.

Clin:

Mutations in the DOCK8 gene result in the autosomal recessive form of hyper-IgE syndrome.

Diseases associated with DOCK8 include:

• Hyper-IgE recurrent infection syndrome, autosomal recessive (OMIM: 243700; Minegishi Y et al. 2006; Renner ED et al. 2004).
• and
• Autosomal Dominant Non-Syndromic Intellectual Disability.

Related signaling pathways include factors involved in megakaryocyte development and platelet production, as well as the response to increased platelet cytosolic Ca2+.

1. Milner JD et al (2008) Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452: 773-776.
2. Minegishi Y et al (2006) Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 25: 745-755.
3. Renner ED et al (2004) Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity. J Pediat 144: 93-99.