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Original article
ADAP2 in heart development: a candidate gene for the occurrence of cardiovascular malformations in NF1 microdeletion syndrome
  1. Marco Venturin1,
  2. Silvia Carra2,
  3. Germano Gaudenzi2,
  4. Silvia Brunelli3,
  5. Guido Roberto Gallo2,
  6. Silvia Moncini1,
  7. Franco Cotelli2,
  8. Paola Riva1
  1. 1Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy
  2. 2Dipartimento di Bioscienze, Università degli Studi di Milano, Milan, Italy
  3. 3Dipartimento di Scienze della Salute, Università degli Studi di Milano-Bicocca, Monza (MB), Italy
  1. Correspondence to Dr Marco Venturin, Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano; Via Viotti 3/5, Milan 20133, Italy; marco.venturin{at}unimi.it Dr Paola Riva, Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano; Via Viotti 3/5 Milan 20133, Italy; paola.riva@unimi.it

Abstract

Background Cardiovascular malformations have a higher incidence in patients with NF1 microdeletion syndrome compared to NF1 patients with intragenic mutation, presumably owing to haploinsufficiency of one or more genes included in the deletion interval and involved in heart development. In order to identify which genes could be responsible for cardiovascular malformations in the deleted patients, we carried out expression studies in mouse embryos and functional studies in zebrafish.

Methods and results The expression analysis of three candidate genes included in the NF1 deletion interval, ADAP2, SUZ12 and UTP6, performed by in situ hybridisation, showed the expression of ADAP2 murine ortholog in heart during fundamental phases of cardiac morphogenesis. In order to investigate the role of ADAP2 in cardiac development, we performed loss-of-function experiments of zebrafish ADAP2 ortholog, adap2, by injecting two different morpholino oligos (adap2-MO and UTR-adap2-MO). adap2-MOs-injected embryos (morphants) displayed in vivo circulatory and heart shape defects. The molecular characterisation of morphants with cardiac specific markers showed that the injection of adap2-MOs causes defects in heart jogging and looping. Additionally, morphological and molecular analysis of adap2 morphants demonstrated that the loss of adap2 function leads to defective valvulogenesis, suggesting a correlation between ADAP2 haploinsufficiency and the occurrence of valve defects in NF1-microdeleted patients.

Conclusions Overall, our findings indicate that ADAP2 has a role in heart development, and might be a reliable candidate gene for the occurrence of cardiovascular malformations in patients with NF1 microdeletion and, more generally, for the occurrence of a subset of congenital heart defects.

  • Molecular genetics
  • Congenital heart disease

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