Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies

Am J Hum Genet. 2011 May 13;88(5):574-85. doi: 10.1016/j.ajhg.2011.04.013.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Cell Adhesion
  • Cell Movement
  • Cell Polarity
  • Cell Proliferation
  • Chromosome Mapping
  • Cytoskeleton / metabolism
  • DNA Mutational Analysis
  • Ectodermal Dysplasia / embryology
  • Ectodermal Dysplasia / genetics*
  • Female
  • GTPase-Activating Proteins / genetics*
  • Gene Expression Regulation
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Limb Deformities, Congenital / embryology
  • Limb Deformities, Congenital / genetics
  • Male
  • Mutation*
  • Scalp Dermatoses / congenital
  • Scalp Dermatoses / embryology
  • Scalp Dermatoses / genetics
  • Signal Transduction
  • cdc42 GTP-Binding Protein / metabolism
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Actins
  • GTPase-Activating Proteins
  • RAC1 protein, human
  • cdc42 GTP-Binding Protein
  • rac1 GTP-Binding Protein

Supplementary concepts

  • Adams Oliver syndrome