Molecular Characteristics
The DOCK6 (Dedicator of Cytokinesis 6) gene is located at 19p13.2 and encodes an atypical guanidine exchange factor, which activates Cdc42 and Rac1, members of the Rho GTPase family. Cdc42 and Rac1 play a role in several cellular processes, such as polarization, proliferation, migration, secretion, adhesion, apoptosis, phagocytosis, and maintenance of cell morphology, through induced polymerization of actin filaments. Shaheen et al. (2011) detected Dock6 expression in the lung, heart, and growing edge of limb buds and developing digits of the mouse. Nohata et al. (2016) also showed that Rac1 is necessary in endothelial sprouting in retinal vasculature in the mouse, likely explaining why ocular abnormalities in AOS have only been reported when DOCK6 mutations are present (Hassed et al. 2017).
Mutations and pathophysiology
Mutations in DOCK6 lead to the inactivation of Cdc42 and Rac1A. A few selected examples of pathogenic variants are described below:
Shaheen et al. (2011) reported two DOCK6 (GenBank NM_020812.3) mutations in two unrelated individuals from consanguineous families:
- 1362_1365delAACT (p.Thr455Serfs*24) homozygous 4bp deletion mutation
- 1245dupT (p.Asp416*) homozygous mutation creating a stop codon
Shaheen et al. (2013) again reported two additional homozygous DOCK6 mutations:
- 2520dupT (p.Arg841Serfs∗6) resulting in frameshift and premature stop codon
- 4107-1G>C (p.Thr1370Metfs∗19) leading to frameshift and introduction of a premature stop codon
Sukalo et al. (2015) and Meester et al. (2018) reported additional 7 homozygous mutations:
- 484G > T (p.Glu162*)
- 1296_1297delinsT (p.Gln434Argfs*21)
- 2520dupT (p.Arg841Serfs*6)
- 3047T > C (p.Leu1016Pro)
- 3154G > A (p.Glu1052Lys)
- 4786C > T (p.Arg1596Trp)
- c.5235+205_6102‐15delinsCATGGGGCTG (4.3 kb deletion)