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

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 (approximately 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.

A variant in the carboxyl-terminus of connexin 40 alters GAP junctions and increases risk for tetralogy of Fallot

“…However, mutations in these genes have been related also to other CHDs. 8,9,[15][16][17] In addition, large de novo copy number variants have been implicated as a cause of non-syndromic TOF. 18 Among these, a copy number variant at chromosome 1q21.1 was found in 1% of non-syndromic sporadic TOF cases.…”

Loss of procollagen IIA from the anterior mesendoderm disrupts the development of mouse embryonic forebrain

“…Recently, combinations of HPE and congenital heart defects are shown to associate with mutations of components of NODAL pathway such as NODAL, CFC1, SMAD2, and FOXH1 (Roessler et al, 2008(Roessler et al, , 2009. Mutations in the COL2A1 gene are associated with type II collagenopathies (Freisinger et al, 1996), which include a variable degree of midface hypoplasia (Snead and Yates, 1999), one of the features of HPE.…”

Nodal Signaling and Congenital Heart Defects

“…Congenital heart defects have also been linked to aberrant Nodal signaling (Table 24.1) [36]. Loss-of-function mutations in genes encoding numerous Nodal signaling components, including Nodal, Cripto, Cryptic, and FoxH1, have been identified in patients with heart defects [37,38]. The spectrum of heart defects in these patients can be roughly grouped into two broadly defined classes: (1) those that occur as a result of overall isomerism or heterotaxy and (2) those that occur as isolated congenital heart defects.…”