Southgate, Laura and Machado, Rajiv D. and Snape, Katie M and Primeau, Martin and Dafou, Dimitra and Ruddy, Deborah M and Branney, Peter A and Fisher, Malcolm and Lee, Grace J. and Simpson, Michael A. and He, Yi and Bradshaw, Teisha Y. and Blaumeiser, Bettina and Winship, William S. and Reardon, Willie and Maher, Eamonn R. and FitzPatrick, David R. and Wuyts, Wim and Zenker, Martin and Lamarche-Vane, Nathalie and Trembath, Richard C. (2011) Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies. American Journal of Human Genetics, 88 (5). pp. 574-85. ISSN 0002-9297

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Abstract

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.

Item Type:	Article
Keywords:	Adams-Oliver syndrome, Rho GTPases, Gene identification, ref03, refdoi
Subjects:	C Biological Sciences > C431 Medical Genetics
Divisions:	College of Sciences > Faculty of Science > School of Life Sciences
Depositing User:	Rajiv Machado
Date Deposited:	27 Sep 2012 16:44
Last Modified:	03 May 2013 10:28
URI:	http://eprints.lincoln.ac.uk/id/eprint/6311

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