A mechanism for gene-environment interaction in the etiology of congenital scoliosis.
Sparrow DB., Chapman G., Smith AJ., Mattar MZ., Major JA., O'Reilly VC., Saga Y., Zackai EH., Dormans JP., Alman BA., McGregor L., Kageyama R., Kusumi K., Dunwoodie SL.
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.