Loss-of-function mutations in growth differentiation factor-1 (GDF1) are associated with congenital heart defects in humans.
Congenital heart defects (CHDs) are among the most common birth defects in humans (incidence 8-10 per 1,000 live births). Although their etiology is often poorly understood, most are considered to arise from multifactorial influences, including environmental and genetic components, as well as from less common syndromic forms. We hypothesized that disturbances in left-right patterning could contribute to the pathogenesis of selected cardiac defects by interfering with the extrinsic cues leading to the proper looping and vessel remodeling of the normally asymmetrically developed heart and vessels. Here, we show that heterozygous loss-of-function mutations in the human GDF1 gene contribute to cardiac defects ranging from tetralogy of Fallot to transposition of the great arteries and that decreased TGF- beta signaling provides a framework for understanding their pathogenesis. These findings implicate perturbations of the TGF- beta signaling pathway in the causation of a major subclass of human CHDs.
Karkera
J D
JD
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Lee
J S
JS
Roessler
E
E
Banerjee-Basu
S
S
Ouspenskaia
M V
MV
Mez
J
J
Goldmuntz
E
E
Bowers
P
P
Towbin
J
J
Belmont
J W
JW
Baxevanis
A D
AD
Schier
A F
AF
Muenke
M
M
D000595:Amino Acid Sequence; D000818:Animals; D004252:DNA Mutational Analysis; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D055452:Growth Differentiation Factor 1; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D017433:Protein Structure, Secondary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
C525977:GDF1 protein, human; C525978:Gdf1 protein, mouse; D055452:Growth Differentiation Factor 1; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger