Reduced NODAL Signaling Strength via Mutation of Several Pathway Members Including FOXH1 Is Linked to Human Heart Defects and Holoprosencephaly

Erich Roessler, Maia V. Ouspenskaia, Jayaprakash D. Karkera, Jorge I. Vélez, Amy Kantipong, Felicitas Lacbawan, Peter Bowers, John W. Belmont, Jeffrey Towbin, Elizabeth Goldmuntz, Benjamin Feldman, Maximilian Muenke

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

Abnormalities of embryonic patterning are hypothesized to underlie many common congenital malformations in humans including congenital heart defects (CHDs), left-right disturbances (L-R) or laterality, and holoprosencephaly (HPE). Studies in model organisms suggest that Nodal-like factors provide instructions for key aspects of body axis and germ layer patterning; however, the complex genetics of pathogenic gene variant(s) in humans are poorly understood. Here we report our studies of FOXH1, CFC1, and SMAD2 and summarize our mutational analysis of three additional components in the human NODAL-signaling pathway: NODAL, GDF1, and TDGF1. We identify functionally abnormal gene products throughout the pathway that are clearly associated with CHD, laterality, and HPE. Abnormal gene products are most commonly detected in patients within a narrow spectrum of isolated conotruncal heart defects (minimum 5%-10% of subjects), and far less commonly in isolated laterality or HPE patients (∼1% for each). The difference in the mutation incidence between these groups is highly significant. We show that apparent gene dosage discrepancies between humans and model organisms can be reconciled by considering a broader combination of sequence variants. Our studies confirm that (1) the genetic vulnerabilities inferred from model organisms with defects in Nodal signaling are indeed analogous to humans; (2) the molecular analysis of an entire signaling pathway is more complete and robust than that of individual genes and presages future studies by whole-genome analysis; and (3) a functional genomics approach is essential to fully appreciate the complex genetic interactions necessary to produce these effects in humans.

Original languageEnglish (US)
Pages (from-to)18-29
Number of pages12
JournalAmerican Journal of Human Genetics
Volume83
Issue number1
DOIs
StatePublished - Jul 11 2008
Externally publishedYes

Fingerprint

Holoprosencephaly
Mutation
Congenital Heart Defects
Genes
Germ Layers
Gene Dosage
Genomics
Genome
Incidence

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Reduced NODAL Signaling Strength via Mutation of Several Pathway Members Including FOXH1 Is Linked to Human Heart Defects and Holoprosencephaly. / Roessler, Erich; Ouspenskaia, Maia V.; Karkera, Jayaprakash D.; Vélez, Jorge I.; Kantipong, Amy; Lacbawan, Felicitas; Bowers, Peter; Belmont, John W.; Towbin, Jeffrey; Goldmuntz, Elizabeth; Feldman, Benjamin; Muenke, Maximilian.

In: American Journal of Human Genetics, Vol. 83, No. 1, 11.07.2008, p. 18-29.

Research output: Contribution to journalArticle

Roessler, E, Ouspenskaia, MV, Karkera, JD, Vélez, JI, Kantipong, A, Lacbawan, F, Bowers, P, Belmont, JW, Towbin, J, Goldmuntz, E, Feldman, B & Muenke, M 2008, 'Reduced NODAL Signaling Strength via Mutation of Several Pathway Members Including FOXH1 Is Linked to Human Heart Defects and Holoprosencephaly', American Journal of Human Genetics, vol. 83, no. 1, pp. 18-29. https://doi.org/10.1016/j.ajhg.2008.05.012
Roessler, Erich ; Ouspenskaia, Maia V. ; Karkera, Jayaprakash D. ; Vélez, Jorge I. ; Kantipong, Amy ; Lacbawan, Felicitas ; Bowers, Peter ; Belmont, John W. ; Towbin, Jeffrey ; Goldmuntz, Elizabeth ; Feldman, Benjamin ; Muenke, Maximilian. / Reduced NODAL Signaling Strength via Mutation of Several Pathway Members Including FOXH1 Is Linked to Human Heart Defects and Holoprosencephaly. In: American Journal of Human Genetics. 2008 ; Vol. 83, No. 1. pp. 18-29.
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