RESUMO
Notch signaling regulates a vast array of crucial developmental processes. It is therefore not surprising that mutations in genes encoding Notch receptors or ligands lead to a variety of congenital disorders in humans. For example, loss of function of Notch results in Adams-Oliver syndrome, Alagille syndrome, spondylocostal dysostosis and congenital heart disorders, while Notch gain of function results in Hajdu-Cheney syndrome, serpentine fibula polycystic kidney syndrome, infantile myofibromatosis and lateral meningocele syndrome. Furthermore, structure-abrogating mutations in NOTCH3 result in CADASIL. Here, we discuss these human congenital disorders in the context of known roles for Notch signaling during development. Drawing on recent analyses by the exome aggregation consortium (EXAC) and on recent studies of Notch signaling in model organisms, we further highlight additional Notch receptors or ligands that are likely to be involved in human genetic diseases.
Assuntos
Doenças Genéticas Inatas/embriologia , Doenças Genéticas Inatas/genética , Receptores Notch/genética , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/genética , Síndrome de Alagille/embriologia , Síndrome de Alagille/genética , Animais , Biologia do Desenvolvimento , Displasia Ectodérmica/embriologia , Displasia Ectodérmica/genética , Síndrome de Hajdu-Cheney/embriologia , Síndrome de Hajdu-Cheney/genética , Hérnia Diafragmática/embriologia , Hérnia Diafragmática/genética , Humanos , Deformidades Congênitas dos Membros/embriologia , Deformidades Congênitas dos Membros/genética , Meningocele/embriologia , Meningocele/genética , Dermatoses do Couro Cabeludo/congênito , Dermatoses do Couro Cabeludo/embriologia , Dermatoses do Couro Cabeludo/genéticaAssuntos
Anormalidades Múltiplas/patologia , Displasia Ectodérmica/patologia , Deformidades Congênitas dos Membros/patologia , Dermatoses do Couro Cabeludo/congênito , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/genética , Adolescente , Vasos Sanguíneos/embriologia , Criança , Consanguinidade , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/embriologia , Displasia Ectodérmica/genética , Feminino , Deformidades Congênitas do Pé/genética , Humanos , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/embriologia , Deformidades Congênitas dos Membros/genética , Masculino , Dermatoses do Couro Cabeludo/diagnóstico , Dermatoses do Couro Cabeludo/embriologia , Dermatoses do Couro Cabeludo/genética , Dermatoses do Couro Cabeludo/patologiaRESUMO
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.