Transcriptional deregulation and a missense mutation define ANKRD1 as a candidate gene for total anomalous pulmonary venous return
Articolo
Data di Pubblicazione:
2008
Citazione:
Transcriptional deregulation and a missense mutation define ANKRD1 as a candidate gene for total anomalous pulmonary venous return / R. Cinquetti, I. Badi, M. Campione, E. Bortoletto, G. Chiesa, C. Parolini, C. Camesasca, A. Russo, R. Taramelli, F. Acquati. - In: HUMAN MUTATION. - ISSN 1059-7794. - 29:4(2008), pp. 468-474. [10.1002/humu.20711]
Abstract:
Total anomalous pulmonary venous return (TAPVR) is a congenital heart defect in which the pulmonary veins fail to enter the left atrium and drain instead into the right atrium or one of its venous tributaries. Although a genetic basis for TAPVR has long been recognized, no single gene involved in the pathogenesis of this disease has been identified to date. We previously reported a TAPVR patient bearing a de novo 10;21 balanced translocation. In this work, we cloned both translocation breakpoints from this patient and mapped the ANKRD1 gene, encoding a cardiac transcriptional regulator, 130 kb proximally to the breakpoint on chromosome 10. In situ hybridization analysis performed on murine embryos showed ANKRD1 expression in the developing pulmonary veins, suggesting a possible role for this gene in TAPVR pathogenesis. Moreover, ANKRD1 expression levels were found to be highly increased in lymphoblastoid cell lines derived from both the translocation-bearing proband and a second independent sporadic TAPVR patient, suggesting that disruption of the normal ANKRD1 expression pattern is associated with TAPVR. Finally, a nonconservative missense mutation in the ANKRD1 gene was found in a third sporadic TAPVR patient. In vitro calpain-mediated degradation assays, coupled to reporter gene analysis in transfected HeLa cells, strongly suggested that this mutation enhances both the stability of the ANKRD1/CARP protein and its transcriptional repression activity upon the cardiac-specific atrial natriuretic factor (ANF) promoter. Taken together, these results define ANKRD1 as a possible candidate gene for TAPVR pathogenesis.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
ANKRD1; Candidate gene; Congenital heart disease; TAPVR
Elenco autori:
R. Cinquetti, I. Badi, M. Campione, E. Bortoletto, G. Chiesa, C. Parolini, C. Camesasca, A. Russo, R. Taramelli, F. Acquati
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