Author/Authors :
Duncan B. Sparrow، نويسنده , , Gavin Chapman، نويسنده , , Allanceson J. Smith، نويسنده , , Muhammad Z. Mattar، نويسنده , , Joelene A. Major، نويسنده , , Victoria C. OʹReilly، نويسنده , , Yumiko Saga، نويسنده , , Elaine H. Zackai، نويسنده , , John P. Dormans، نويسنده , , Benjamin A. Alman، نويسنده , , Lesley McGregor، نويسنده , , Ryoichiro Kageyama، نويسنده , , Kenro Kusumi، نويسنده , , Sally L. Dunwoodie، نويسنده ,
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.
