A mechanism for gene-environment interaction in the etiology of congenital scoliosis.
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.
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
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