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© American Heart Association, Inc.

Clinical Investigation and Reports

Missense Mutations and Gene Interruption in PROSIT240, a Novel TRAP240-Like Gene, in Patients With Congenital Heart Defect (Transposition of the Great Arteries)

From the Institut für Humangenetik (N.M., C.G., R.R., A.H., K.S., G.R.), Universität Heidelberg, and the Abteilung für Kardiologie (H.R., H.U.), Kinderklinik Heidelberg, Heidelberg, Germany; the Division of Cardiology (E.G., D.D.), Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pa; and the Institute of Human Genetics (J.G.), International Center for Life, Newcastle upon Tyne, Great Britain.

Correspondence to Gudrun Rappold, PhD, Institute of Human Genetics, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany. E-mail gudrun_rappold{at}med.uni-heidelberg.de

Received August 8, 2003; de novo received September 17, 2003; accepted October 9, 2003.

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.

Key Words: transposition of great vessels • heart defects, congenital • heart diseases

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