title: A mechanism for gene-environment interaction in the etiology of congenital scoliosis.
abstract: Congenital scoliosis, a lateral curvature of the spine caused by vertebral defects, occurs in approximately 1 in 1,000 live births. Here we demonstrate that haploinsufficiency of Notch signaling pathway genes in humans can cause this congenital abnormality. We also show that in a mouse model, the combination of this genetic risk factor with an environmental condition (short-term gestational hypoxia) significantly increases the penetrance and severity of vertebral defects. We demonstrate that hypoxia disrupts FGF signaling, leading to a temporary failure of embryonic somitogenesis. Our results potentially provide a mechanism for the genesis of a host of common sporadic congenital abnormalities through gene-environment interaction.
authors.affiliation: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia. d.sparrow@victorchang.edu.au
authors.forename: Duncan B
authors.initials: DB
authors.lastname: Sparrow
authors.forename: Gavin
authors.initials: G
authors.lastname: Chapman
authors.forename: Allanceson J
authors.initials: AJ
authors.lastname: Smith
authors.forename: Muhammad Z
authors.initials: MZ
authors.lastname: Mattar
authors.forename: Joelene A
authors.initials: JA
authors.lastname: Major
authors.forename: Victoria C
authors.initials: VC
authors.lastname: O'Reilly
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Saga
authors.forename: Elaine H
authors.initials: EH
authors.lastname: Zackai
authors.forename: John P
authors.initials: JP
authors.lastname: Dormans
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Alman
authors.forename: Lesley
authors.initials: L
authors.lastname: McGregor
authors.forename: Ryoichiro
authors.initials: R
authors.lastname: Kageyama
authors.forename: Kenro
authors.initials: K
authors.lastname: Kusumi
authors.forename: Sally L
authors.initials: SL
authors.lastname: Dunwoodie
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D059647:Gene-Environment Interaction; D057895:Haploinsufficiency; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D008297:Male; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010375:Pedigree; D019683:Penetrance; D051880:Receptors, Notch / Q000378:metabolism; D012600:Scoliosis / Q000151:congenital / Q000196:embryology*; D015398:Signal Transduction; D013131:Spine / Q000196:embryology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051880:Receptors, Notch; C486601:HES7 protein, human; C430525:Hes7 protein, mouse; C572576:MESP2 protein, human; C107407:Mesp2 protein, mouse