Cumulative ligand activity of NODAL mutations and modifiers are linked to human heart defects and holoprosencephaly

Erich Roessler, Wuhong Pei, Maia V. Ouspenskaia, Jayaprakash D. Karkera, Jorge Ivan Veléz, Sharmilla Banerjee-Basu, Gretchen Gibney, Philip J. Lupo, Laura E. Mitchell, Jeffrey Towbin, Peter Bowers, John W. Belmont, Elizabeth Goldmuntz, Andreas D. Baxevanis, Benjamin Feldman, Maximilian Muenke

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

The cyclopic and laterality phenotypes in model organisms linked to disturbances in the generation or propagation of Nodal-like signals are potential examples of similar impairments resulting in birth defects in humans. However, the types of gene mutation(s) and their pathogenetic combinations in humans are poorly understood. Here we describe a mutational analysis of the human NODAL gene in a large panel of patients with phenotypes compatible with diminished NODAL ligand function. Significant reductions in the biological activity of NODAL alleles are detected among patients with congenital heart defects (CHD), laterality anomalies (e.g. left-right mis-specification phenotypes), and only rarely holoprosencephaly (HPE). While many of these NODAL variants are typical for family-specific mutations, we also report the presence of alleles with significantly reduced activity among common population variants. We propose that some of these common variants act as modifiers and contribute to the ultimate phenotypic outcome in these patients; furthermore, we draw parallels with strain-specific modifiers in model organisms to bolster this interpretation.

Original languageEnglish (US)
Pages (from-to)225-234
Number of pages10
JournalMolecular Genetics and Metabolism
Volume98
Issue number1-2
DOIs
StatePublished - Oct 1 2009
Externally publishedYes

Fingerprint

Holoprosencephaly
Genes
Ligands
Phenotype
Defects
Mutation
Bioactivity
Alleles
Congenital Heart Defects
Specifications
Population

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

Cite this

Roessler, E., Pei, W., Ouspenskaia, M. V., Karkera, J. D., Veléz, J. I., Banerjee-Basu, S., ... Muenke, M. (2009). Cumulative ligand activity of NODAL mutations and modifiers are linked to human heart defects and holoprosencephaly. Molecular Genetics and Metabolism, 98(1-2), 225-234. https://doi.org/10.1016/j.ymgme.2009.05.005

Cumulative ligand activity of NODAL mutations and modifiers are linked to human heart defects and holoprosencephaly. / Roessler, Erich; Pei, Wuhong; Ouspenskaia, Maia V.; Karkera, Jayaprakash D.; Veléz, Jorge Ivan; Banerjee-Basu, Sharmilla; Gibney, Gretchen; Lupo, Philip J.; Mitchell, Laura E.; Towbin, Jeffrey; Bowers, Peter; Belmont, John W.; Goldmuntz, Elizabeth; Baxevanis, Andreas D.; Feldman, Benjamin; Muenke, Maximilian.

In: Molecular Genetics and Metabolism, Vol. 98, No. 1-2, 01.10.2009, p. 225-234.

Research output: Contribution to journalArticle

Roessler, E, Pei, W, Ouspenskaia, MV, Karkera, JD, Veléz, JI, Banerjee-Basu, S, Gibney, G, Lupo, PJ, Mitchell, LE, Towbin, J, Bowers, P, Belmont, JW, Goldmuntz, E, Baxevanis, AD, Feldman, B & Muenke, M 2009, 'Cumulative ligand activity of NODAL mutations and modifiers are linked to human heart defects and holoprosencephaly', Molecular Genetics and Metabolism, vol. 98, no. 1-2, pp. 225-234. https://doi.org/10.1016/j.ymgme.2009.05.005
Roessler, Erich ; Pei, Wuhong ; Ouspenskaia, Maia V. ; Karkera, Jayaprakash D. ; Veléz, Jorge Ivan ; Banerjee-Basu, Sharmilla ; Gibney, Gretchen ; Lupo, Philip J. ; Mitchell, Laura E. ; Towbin, Jeffrey ; Bowers, Peter ; Belmont, John W. ; Goldmuntz, Elizabeth ; Baxevanis, Andreas D. ; Feldman, Benjamin ; Muenke, Maximilian. / Cumulative ligand activity of NODAL mutations and modifiers are linked to human heart defects and holoprosencephaly. In: Molecular Genetics and Metabolism. 2009 ; Vol. 98, No. 1-2. pp. 225-234.
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