Recessive Mutations in DOCK6, Encoding the Guanidine Nucleotide Exchange Factor DOCK6, Lead to Abnormal Actin Cytoskeleton Organization and Adams-Oliver.

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Recessive Mutations in DOCK6, Encoding the Guanidine Nucleotide Exchange Factor DOCK6, Lead to Abnormal Actin Cytoskeleton Organization and Adams-Oliver Syndrome Ranad Shaheen, Eissa Faqeih, Asma Sunker, Heba Morsy, Tarfa Al-Sheddi, Hanan E. Shamseldin, Nouran Adly, Mais Hashem, Fowzan S. Alkuraya. The American Journal of Human Genetics Volume 89, Issue 2, Pages 328-333 (August 2011) DOI: 10.1016/j.ajhg.2011.07.009 Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees of the Two AOS Families Included in the Study and Clinical Photographs of Individuals 1 and 2 (A) Family 1 pedigree. (B) Clinical photographs of individual 1. (C) Family 2 pedigree. (D) Clinical photographs of individual 2. Note the typical ACC and TTLD in both individuals. The American Journal of Human Genetics 2011 89, 328-333DOI: (10.1016/j.ajhg.2011.07.009) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 2 Identification of Two DOCK6 Mutations in AOS Upper panel: Diagram of DOCK6 (triangles indicate the sites of the mutations). Middle panel: Diagram of DOCK6 (note that both truncating mutations are upstream of DHR-1 and DHR-2 domains). Bottom panel: Sequence chromatogram of the two mutations with the control tracing for comparison (sequence differences are underlined in red). The American Journal of Human Genetics 2011 89, 328-333DOI: (10.1016/j.ajhg.2011.07.009) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 3 WISH of Dock6 during Mouse Embryonic Development (A) E9.5 mouse embryo showing expression in the growing edge of the limb bud. (B) E10.5 mouse embryo showing expression in the growing edge of limb buds and heart. (C) E11.5 mouse embryo showing expression in the apical ectodermal ridge of all four limbs (arrowheads and inset) as well as the first-pharyngeal-arch-derived facial mesenchyme (triangles). (D and E) E12.5 and 13.5 embryos showing the diffuse expression of Dock6 mRNA in the fore- and hind-limbs. (F and G) Close-up view showing the expression in the limbs of an E13.5 embryo. (H and I) Sense control for comparison with (F) and (G). The American Journal of Human Genetics 2011 89, 328-333DOI: (10.1016/j.ajhg.2011.07.009) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 4 Patient and Control Fibroblast Cells Were Visualized by Fluorescent Microscopy for Phalloidin Staining of F-actin- and DAPI-Stained Nuclei F-actin staining is in red, and DAPI staining is in blue. (A and B) Control fibroblasts (A) show the typical spindle appearance, whereas patient fibroblasts (B) show relatively high frequency of rounded (solid arrowheads) and elongated (empty arrows heads) cells. (C) A close-up view of one patient fibroblast with a rounded phenotype clearly indicates blebbing (arrow heads). (D and E) The normal appearance of lamellopodia in control fibroblasts (D) is in sharp contrast to the “blunt” edges due to severe deficiency of lamellopodia formation in patient fibroblasts (E). The American Journal of Human Genetics 2011 89, 328-333DOI: (10.1016/j.ajhg.2011.07.009) Copyright © 2011 The American Society of Human Genetics Terms and Conditions