Gain-of-Function Mutations of ARHGAP31, a Cdc42/Rac1 GTPase Regulator, Cause Syndromic Cutis Aplasia and Limb Anomalies
574 - 585
AM J HUM GENET
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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 through effects upon 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 a region of chromosome 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 (ARHGAP31) gene, 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, closely mirroring the sites of impaired organogenesis that characterize this syndrome. These data identify the requirement for regulated Cdc42/Rac1 signaling processes during early human development.
AuthorsSouthgate, L; Machado, RD; Snape, KM; Primeau, M; Dafou, D; Ruddy, DM; Branney, PA; Fisher, M; Lee, GJ; Simpson, MA; He, Y; Bradshaw, TY; Blaumeiser, B; Winship, WS; Reardon, W; Maher, ER; FitzPatrick, DR; Wuyts, W; Zenker, M; Lamarche-Vane, N; Trembath, RC
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