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1096-7206981-22009Sep-OctMolecular genetics and metabolismMol Genet MetabCumulative ligand activity of NODAL mutations and modifiers are linked to human heart defects and holoprosencephaly.225234225-3410.1016/j.ymgme.2009.05.005The 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.RoesslerErichEMedical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-3717, USA.PeiWuhongWOuspenskaiaMaia VMVKarkeraJayaprakash DJDVelézJorge IvanJIBanerjee-BasuSharmillaSGibneyGretchenGLupoPhilip JPJMitchellLaura ELETowbinJeffrey AJABowersPeterPBelmontJohn WJWGoldmuntzElizabethEBaxevanisAndreas DADFeldmanBenjaminBMuenkeMaximilianMengRefSeqNM_001492NM_018055P50 HL074731HLNHLBI NIH HHSUnited StatesZ01 HG000209ImNIHIntramural NIH HHSUnited StatesP50 HL74731HLNHLBI NIH HHSUnited StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, N.I.H., Intramural20090527
United StatesMol Genet Metab98054561096-71920GDF1 protein, human0Growth Differentiation Factor 10Ligands0NODAL protein, human0Nodal Protein0Transforming Growth Factor betaIMAllelesAmino Acid SequenceFamilyGrowth Differentiation Factor 1chemistryHeart Defects, CongenitalcomplicationsgeneticsHoloprosencephalycomplicationsgeneticsHumansLigandsMolecular Sequence DataMutationgeneticsNodal ProteinchemistrygeneticsPolymorphism, GeneticProtein Structure, TertiarySequence Homology, Amino AcidSignal TransductionTransforming Growth Factor betachemistryCONFLICT OF INTEREST STATEMENT. None declared.20095132009519200962690200962690200911660201091ppublish19553149NIHMS119971PMC277483910.1016/j.ymgme.2009.05.005S1096-7192(09)00138-3Muenke M, Beachy PA. Holoprosencephaly. In: Scriver CR, Beaudet AL, Valle D, Sly WS, editors. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill; 2001. pp. 6203–6230.Roessler E, Muenke M. 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