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 Jefferies, William J. Craigen, Jeffrey Towbin, John W. Belmont, Stephanie M. Ware

Research output: Contribution to journalArticle

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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-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
Volume18
Issue number5
DOIs
StatePublished - Feb 25 2009
Externally publishedYes

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Mutation
Gene Components
Pulmonary Atresia
Cell Nucleus Active Transport
Vertebrates
Embryonic Structures
Phosphorylation
Proteins

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations. / Mohapatra, Bhagyalaxmi; Casey, Brett; Li, Hua; Ho-Dawson, Trang; Smith, Liana; Fernbach, Susan D.; Molinari, Laura; Niesh, Stephen R.; Jefferies, John; Craigen, William J.; Towbin, Jeffrey; Belmont, John W.; Ware, Stephanie M.

In: Human Molecular Genetics, Vol. 18, No. 5, 25.02.2009, p. 861-871.

Research output: Contribution to journalArticle

Mohapatra, B, Casey, B, Li, H, Ho-Dawson, T, Smith, L, Fernbach, SD, Molinari, L, Niesh, SR, Jefferies, J, Craigen, WJ, Towbin, J, Belmont, JW & Ware, SM 2009, 'Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations', Human Molecular Genetics, vol. 18, no. 5, pp. 861-871. https://doi.org/10.1093/hmg/ddn411
Mohapatra, Bhagyalaxmi ; Casey, Brett ; Li, Hua ; Ho-Dawson, Trang ; Smith, Liana ; Fernbach, Susan D. ; Molinari, Laura ; Niesh, Stephen R. ; Jefferies, John ; Craigen, William J. ; Towbin, Jeffrey ; Belmont, John W. ; Ware, Stephanie M. / Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations. In: Human Molecular Genetics. 2009 ; Vol. 18, No. 5. pp. 861-871.
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