期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 88, 期 5, 页码 574-585出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2011.04.013
关键词
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资金
- British Heart Foundation (BHF) [RG/08/006/25302]
- Wellcome Trust [078751/Z/05/Z]
- European Union [LSHM-CT-2005-018725]
- Canadian Institute of Health Research [MOP-84449]
- German Research Foundation [ZE 524/2-2]
- Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre
- St Thomas' NHS Foundation Trust
- King's College London
- King's College Hospital NHS Foundation Trust
- National Institute of Dental and Craniofacial Research (National Institutes of Health) Craniofacial Center [P50 DE-16215-05]
- MRC [MC_U127561093] Funding Source: UKRI
- Wellcome Trust [078751/Z/05/Z] Funding Source: Wellcome Trust
- British Heart Foundation [RG/08/006/25302] Funding Source: researchfish
- Medical Research Council [MC_U127561093] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0507-10379] Funding Source: researchfish
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.
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