BACKGROUND: Congenital heart disease represents the most common severe birth defect, affecting 0.7% to 1% of all neonates, among whom 5% to 7% display transposition of the great arteries (TGA). TGA represents a septation defect of the common outflow tract of the heart, manifesting around the fifth week during embryonic development. Despite its high prevalence, very little is known about the pathogenesis of this disease. METHODS AND RESULTS: Using a positional cloning approach, we isolated a novel gene, PROSIT240 (also termed THRAP2), that is interrupted in a patient with a chromosomal translocation and who displays TGA and mental retardation. High expression of PROSIT240 within the heart (aorta) and brain (cerebellum) was well correlated with the malformations observed in the patient and prompted further analyses. PROSIT240 shows significant homology to the nuclear receptor coactivator TRAP240, suggesting it to be a new component of the thyroid hormone receptor-associated protein (TRAP) complex. Interestingly, several TRAP components have been previously shown to be important in early embryonic development in various organisms, making PROSIT240 an excellent candidate gene to be correlated to the patient's phenotype. Subsequent mutational screening of 97 patients with isolated dextro-looped TGA revealed 3 missense mutations in PROSIT240, which were not detected in 400 control chromosomes. CONCLUSIONS: Together, these genetic data suggest that PROSIT240 is involved in early heart and brain development.
BACKGROUND:Congenital heart disease represents the most common severe birth defect, affecting 0.7% to 1% of all neonates, among whom 5% to 7% display transposition of the great arteries (TGA). TGA represents a septation defect of the common outflow tract of the heart, manifesting around the fifth week during embryonic development. Despite its high prevalence, very little is known about the pathogenesis of this disease. METHODS AND RESULTS: Using a positional cloning approach, we isolated a novel gene, PROSIT240 (also termed THRAP2), that is interrupted in a patient with a chromosomal translocation and who displays TGA and mental retardation. High expression of PROSIT240 within the heart (aorta) and brain (cerebellum) was well correlated with the malformations observed in the patient and prompted further analyses. PROSIT240 shows significant homology to the nuclear receptor coactivator TRAP240, suggesting it to be a new component of the thyroid hormone receptor-associated protein (TRAP) complex. Interestingly, several TRAP components have been previously shown to be important in early embryonic development in various organisms, making PROSIT240 an excellent candidate gene to be correlated to the patient's phenotype. Subsequent mutational screening of 97 patients with isolated dextro-looped TGA revealed 3 missense mutations in PROSIT240, which were not detected in 400 control chromosomes. CONCLUSIONS: Together, these genetic data suggest that PROSIT240 is involved in early heart and brain development.
Authors: Matthew T Knuesel; Krista D Meyer; Aaron J Donner; Joaquin M Espinosa; Dylan J Taatjes Journal: Mol Cell Biol Date: 2008-12-01 Impact factor: 4.272
Authors: Mary Ella Pierpont; Martina Brueckner; Wendy K Chung; Vidu Garg; Ronald V Lacro; Amy L McGuire; Seema Mital; James R Priest; William T Pu; Amy Roberts; Stephanie M Ware; Bruce D Gelb; Mark W Russell Journal: Circulation Date: 2018-11-20 Impact factor: 29.690
Authors: Abidemi Adegbola; Luciana Musante; Bert Callewaert; Patricia Maciel; Hao Hu; Bertrand Isidor; Sylvie Picker-Minh; Cedric Le Caignec; Barbara Delle Chiaie; Olivier Vanakker; Björn Menten; Annelies Dheedene; Nele Bockaert; Filip Roelens; Karin Decaestecker; João Silva; Gabriela Soares; Fátima Lopes; Hossein Najmabadi; Kimia Kahrizi; Gerald F Cox; Steven P Angus; John F Staropoli; Ute Fischer; Vanessa Suckow; Oliver Bartsch; Andrew Chess; Hans-Hilger Ropers; Thomas F Wienker; Christoph Hübner; Angela M Kaindl; Vera M Kalscheuer Journal: Eur J Hum Genet Date: 2015-03-11 Impact factor: 4.246