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- Title
Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations.
- Authors
Mohapatra, Bhagyalaxmi; Casey, Brett; Li, Hua; Ho-Dawson, Trang; Smith, Liana; Fernbach, Susan D; Molinari, Laura; Niesh, Stephen R; Jefferies, John Lynn; Craigen, William J; Towbin, Jeffrey A; Belmont, John W; Ware, Stephanie M
- Abstract
NODAL and its signaling pathway are known to play a key role in specification and patterning of vertebrate embryos. Mutations in several genes encoding components of the NODAL signaling pathway have previously been implicated in the pathogenesis of human left-right (LR) patterning defects. Therefore, NODAL, a member of TGF-beta superfamily of developmental regulators, is a strong candidate to be functionally involved in congenital LR axis patterning defects or heterotaxy. Here we have investigated whether variants in NODAL are present in patients with heterotaxy and/or isolated cardiovascular malformations (CVM) thought to be caused by abnormal heart tube looping. Analysis of a large cohort of cases (n = 269) affected with either classic heterotaxy or looping CVM revealed four different missense variants, one in-frame insertion/deletion and two conserved splice site variants in 14 unrelated subjects (14/269, 5.2%). Although similar with regard to other associated defects, individuals with the NODAL mutations had a significantly higher occurrence of pulmonary valve atresia (P = 0.001) compared with cases without a detectable NODAL mutation. Functional analyses demonstrate that the missense variant forms of NODAL exhibit significant impairment of signaling as measured by decreased Cripto (TDGF-1) co-receptor-mediated activation of artificial reporters. Expression of these NODAL proteins also led to reduced induction of Smad2 phosphorylation and impaired Smad2 nuclear import. Taken together, these results support a role for mutations and rare deleterious variants in NODAL as a cause for sporadic human LR patterning defects.
- Publication
Human molecular genetics, 2009, Vol 18, Issue 5, p861
- ISSN
1460-2083
- Publication type
Journal Article
- DOI
10.1093/hmg/ddn411