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.
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Animals, Basic Helix-Loop-Helix Transcription Factors, Female, Gene-Environment Interaction, Haploinsufficiency, Humans, Hypoxia, Male, Mesoderm, Mice, Mice, Inbred C57BL, Pedigree, Penetrance, Receptors, Notch, Scoliosis, Signal Transduction, Spine