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

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.

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

“…Holoprosencephaly (HPE; Cohen, 2006;Geng and Oliver, 2009) (Roessler et al, 2009). 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.…”

“…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.…”

NODAL and SHH dose-dependent double inhibition promotes an HPE-like phenotype in chick embryos

“…The NODAL signaling pathway has been implicated in cases of human HPE with or without congenital heart defects and/or left-right disturbances (Roessler et al, 2008;Roessler et al, 2009). NODAL is a transforming growth factor β (TGF-β)-related signaling molecule that is essential during the initiation of…”

“…NODAL signals act in the formation of mesoderm and are required later for correct positioning of the anteroposterior axis, midline patterning and left-right specification (Iannaccone et al, 1992;Zhou et al, 1993;Conlon et al, 1994;Lowe et al, 2001;Roessler et al, 2008;Roessler et al, 2009). The NODAL signaling pathway has been extensively studied during cleavage and blastula stages in zebrafish; NODAL acts in a dose-dependent and time-dependent manner during the mid-to-late blastula stage to specify most mesodermal and endodermal cell types (Hagos and Dougan, 2007;Gritsman et al, 2000).…”