title: Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies.
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.
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, School of Medicine, Guy's Hospital, London, London, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Southgate
authors.forename: Rajiv D
authors.initials: RD
authors.lastname: Machado
authors.forename: Katie M
authors.initials: KM
authors.lastname: Snape
authors.forename: Martin
authors.initials: M
authors.lastname: Primeau
authors.forename: Dimitra
authors.initials: D
authors.lastname: Dafou
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Ruddy
authors.forename: Peter A
authors.initials: PA
authors.lastname: Branney
authors.forename: Malcolm
authors.initials: M
authors.lastname: Fisher
authors.forename: Grace J
authors.initials: GJ
authors.lastname: Lee
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.forename: Yi
authors.initials: Y
authors.lastname: He
authors.forename: Teisha Y
authors.initials: TY
authors.lastname: Bradshaw
authors.forename: Bettina
authors.initials: B
authors.lastname: Blaumeiser
authors.forename: William S
authors.initials: WS
authors.lastname: Winship
authors.forename: Willie
authors.initials: W
authors.lastname: Reardon
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.forename: David R
authors.initials: DR
authors.lastname: FitzPatrick
authors.forename: Wim
authors.initials: W
authors.lastname: Wuyts
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lamarche-Vane
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
mesh_terms: D000199:Actins / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D016764:Cell Polarity; D049109:Cell Proliferation; D002874:Chromosome Mapping; D003599:Cytoskeleton / Q000378:metabolism; D004252:DNA Mutational Analysis; D004476:Ectodermal Dysplasia / Q000196:embryology / Q000235:genetics*; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D017880:Limb Deformities, Congenital / Q000196:embryology / Q000235:genetics; D008297:Male; D009154:Mutation; D012536:Scalp Dermatoses / Q000151:congenital / Q000196:embryology / Q000235:genetics; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D020690:GTPase-Activating Proteins; C107953:RAC1 protein, human; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein