Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations

Bhagyalaxmi Mohapatra, Brett Casey, Hua Li, Trang Ho-Dawson, Liana Smith, Susan D. Fernbach, Laura Molinari, Stephen R. Niesh, John Lynn Jefferies, William J. Craigen, Jeffrey A. Towbin, John W. Belmont, Stephanie M. Ware

Research output: Contribution to journalArticlepeer-review

99 Scopus citations


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-β 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.

Original languageEnglish (US)
Pages (from-to)861-871
Number of pages11
JournalHuman molecular genetics
Issue number5
StatePublished - 2009
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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