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

Laura Southgate, Rajiv D. Machado, Katie M. Snape, Martin Primeau, Dimitra Dafou, Deborah M. Ruddy, Peter A. Branney, Malcolm Fisher, Grace J. Lee, Michael A. Simpson, Yi He, Teisha Y. Bradshaw, Bettina Blaumeiser, William S. Winship, Willie Reardon, Eamonn R. Maher, David R. FitzPatrick, Wim Wuyts, Martin Zenker, Nathalie Lamarche-VaneRichard C. Trembath

Research output: Contribution to journalArticlepeer-review

94 Citations (Scopus)

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. Arhgap37 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.
Original languageEnglish
Pages (from-to)574 - 585
Number of pages12
JournalAmerican Journal of Human Genetics
Volume88
Issue number5
DOIs
Publication statusPublished - 13 May 2011

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