Gain-of-Function Mutations of ARHGAP31, a Cdc42/Rac1 GTPase Regulator, Cause Syndromic Cutis Aplasia and Limb Anomalies

• Published in: American journal of human genetics Vol. 88; no. 5; pp. 574 - 585
• Main Authors: Southgate, Laura, Machado, Rajiv D., Snape, Katie M., Primeau, Martin, Dafou, Dimitra, Ruddy, Deborah M., Branney, Peter A., Fisher, Malcolm, Lee, Grace J., Simpson, Michael A., He, Yi, Bradshaw, Teisha Y., Blaumeiser, Bettina, Winship, William S., Reardon, Willie, Maher, Eamonn R., FitzPatrick, David R., Wuyts, Wim, Zenker, Martin, Lamarche-Vane, Nathalie, Trembath, Richard C.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 13.05.2011; Cell Press; Elsevier
• Subjects: Actins - metabolism; Biological and medical sciences; cdc42 GTP-Binding Protein - metabolism; Cell Adhesion; Cell cycle; Cell Movement; Cell Polarity; Cell Proliferation; Chromosome Mapping; Congenital diseases; Cytoskeleton; Cytoskeleton - metabolism; Dermatology; DNA Mutational Analysis; Ectodermal Dysplasia - embryology; Ectodermal Dysplasia - genetics; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Gene loci; General aspects. Genetic counseling; Genetics of eukaryotes. Biological and molecular evolution; Genomes; GTPase-Activating Proteins - genetics; HEK293 Cells; HeLa Cells; Hereditary diseases of the skin. Congenital diseases of the skin. Haemangioma of the skin, of mucosae and of soft tissue; Humans; Limb Deformities, Congenital - embryology; Limb Deformities, Congenital - genetics; Male; Medical genetics; Medical sciences; Molecular and cellular biology; Mutation; rac1 GTP-Binding Protein - metabolism; Rodents; Scalp Dermatoses - congenital; Scalp Dermatoses - embryology; Scalp Dermatoses - genetics; Signal Transduction; Human; Skin disease; Enzyme; Triphosphoric monoester hydrolases; dGTPase; Esterases; Regulator; Congenital disease; Aplasia cutis; Malformation; Limb; Hydrolases; Genetics; Anomaly; Mutation
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2011.04.013

Regulation of cell proliferation and motility is essential for normal development. The Rho family of GTPases plays a critical role in the control of cell polarity and migration by effecting the cytoskeleton, membrane trafficking, and cell adhesion. We investigated a recognized developmental disorder, Adams-Oliver syndrome (AOS), characterized by the combination of aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD). Through a genome-wide linkage analysis, we detected a locus for autosomal-dominant ACC-TTLD on 3q generating a maximum LOD score of 4.93 at marker rs1464311. Candidate-gene- and exome-based sequencing led to the identification of independent premature truncating mutations in the terminal exon of the Rho GTPase-activating protein 31 gene, ARHGAP31, which encodes a Cdc42/Rac1 regulatory protein. Mutant transcripts are stable and increase ARHGAP31 activity in vitro through a gain-of-function mechanism. Constitutively active ARHGAP31 mutations result in a loss of available active Cdc42 and consequently disrupt actin cytoskeletal structures. Arhgap31 expression in the mouse is substantially restricted to the terminal limb buds and craniofacial processes during early development; these locations closely mirror the sites of impaired organogenesis that characterize this syndrome. These data identify the requirement for regulated Cdc42 and/or Rac1 signaling processes during early human development.