A mechanism for gene-environment interaction in the etiology of congenital scoliosis
Duncan B Sparrow, Gavin Chapman, Allanceson J Smith, Muhammad Z Mattar, Joelene A Major, Victoria C O'Reilly, Yumiko Saga, Elaine H Zackai, John P Dormans, Benjamin A Alman, Lesley McGregor, Ryoichiro Kageyama, Kenro Kusumi, Sally L Dunwoodie, Duncan B Sparrow, Gavin Chapman, Allanceson J Smith, Muhammad Z Mattar, Joelene A Major, Victoria C O'Reilly, Yumiko Saga, Elaine H Zackai, John P Dormans, Benjamin A Alman, Lesley McGregor, Ryoichiro Kageyama, Kenro Kusumi, Sally L Dunwoodie
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.
Copyright © 2012 Elsevier Inc. All rights reserved.
Source: PubMed