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

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...

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Published in:American journal of human genetics 2011-05, Vol.88 (5), p.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: Article
Language:English
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
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Summary: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.
ISSN:0002-9297
1537-6605
DOI:10.1016/j.ajhg.2011.04.013