title: 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.
authors: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-3717, USA.
authors: Erich
authors: E
authors: Roessler
authors: Wuhong
authors: W
authors: Pei
authors: Maia V
authors: MV
authors: Ouspenskaia
authors: Jayaprakash D
authors: JD
authors: Karkera
authors: Jorge Ivan
authors: JI
authors: Veléz
authors: Sharmilla
authors: S
authors: Banerjee-Basu
authors: Gretchen
authors: G
authors: Gibney
authors: Philip J
authors: PJ
authors: Lupo
authors: Laura E
authors: LE
authors: Mitchell
authors: Jeffrey A
authors: JA
authors: Towbin
authors: Peter
authors: P
authors: Bowers
authors: John W
authors: JW
authors: Belmont
authors: Elizabeth
authors: E
authors: Goldmuntz
authors: Andreas D
authors: AD
authors: Baxevanis
authors: Benjamin
authors: B
authors: Feldman
authors: Maximilian
authors: M
authors: Muenke
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D005190:Family; D055452:Growth Differentiation Factor 1 / Q000737:chemistry; D006330:Heart Defects, Congenital / Q000150:complications* / Q000235:genetics*; D016142:Holoprosencephaly / Q000150:complications* / Q000235:genetics*; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D055457:Nodal Protein / Q000737:chemistry / Q000235:genetics*; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000737:chemistry
chemical_list: C525977:GDF1 protein, human; D055452:Growth Differentiation Factor 1; D008024:Ligands; C526007:NODAL protein, human; D055457:Nodal Protein; D016212:Transforming Growth Factor beta