Transcriptional deregulation and a missense mutation define ANKRD1 as a candidate gene for total anomalous pulmonary venous return

Raffaella Cinquetti, Ileana Badi, Marina Campione, Elisabetta Bortoletto, Giulia Chiesa, Cinzia Parolini, Chiara Camesasca, Antonella Russo, Roberto Taramelli, Francesco Acquati

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)468-474
Number of pages7
JournalHuman Mutation
Issue number4
Publication statusPublished - Apr 2008


  • ANKRD1
  • Candidate gene
  • Congenital heart disease

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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