Missense mutations and gene interruption in PROSIT240, a novel TRAP240-like gene, in patients with congenital heart defect (transposition of the great arteries).
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.


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.
Muncke
Nadja
N
Institut für Humangenetik, Universität Heidelberg, Heidelberg, Germany.
Jung
Christine
C
Rüdiger
Heinz
H
Ulmer
Herbert
H
Roeth
Ralph
R
Hubert
Annette
A
Goldmuntz
Elizabeth
E
Driscoll
Deborah
D
Goodship
Judith
J
Schön
Karin
K
Rappold
Gudrun
G
D000015:Abnormalities, Multiple / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D001011:Aorta / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D002524:Cerebellar Ataxia / Q000235:genetics; D002531:Cerebellum / Q000002:abnormalities / Q000378:metabolism; D002648:Child; D002872:Chromosome Deletion; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics* / Q000648:ultrastructure; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics / Q000648:ultrastructure; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D006330:Heart Defects, Congenital / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D056892:Mediator Complex; D008831:Microcephaly / Q000235:genetics; D008969:Molecular Sequence Data; D005810:Multigene Family; D020125:Mutation, Missense; D009928:Organ Specificity; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014178:Translocation, Genetic; D014188:Transposition of Great Vessels / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C480067:MED13L protein, human; D056892:Mediator Complex