<i>ADAP2</i>in heart development: a candidate gene for the occurrence of cardiovascular malformations in NF1 microdeletion syndrome

Venturin, Marco; Carra, Silvia; Gaudenzi, Germano; Brunelli, Silvia; Gallo, Guido Roberto; Moncini, Silvia; Cotelli, Franco; Riva, Paola

doi:10.1136/jmedgenet-2013-102240

Cited by 29 publications

(29 citation statements)

References 31 publications

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“…The heat maps show how genes are clustered across the control and hace1-morpholino knockdown samples (vertical) and along the spectrum and pattern of gene fold changes (horizontal). Similar looping defects were seen in morphants for adap2 (Venturin et al, 2014), slc8a4a (ncx4a) (Shu et al, 2007), and foxj1b . B: Genes associated with "heart development" Gene Ontology term.…”

Section: Discussionsupporting

confidence: 61%

“…The bone morphogenic protein receptors Bmpr2a and Bmpr2b, for example, act upstream of the critical LR regulator Nodal; knockdown of either of these genes causes significant looping defects in affected embryos (Monteiro et al, 2008). Similar looping defects were seen in morphants for adap2 (Venturin et al, 2014), slc8a4a (ncx4a) (Shu et al, 2007), and foxj1b . Interestingly, lmo7 morphants display a similar tubular heart phenotype to our hace1 morphants (Ott et al, 2008).…”

Section: Discussionmentioning

confidence: 93%

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hace1 Influences zebrafish cardiac development via ROS‐dependent mechanisms

Razaghi

Steele

Prykhozhij

et al. 2017

Developmental Dynamics

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 93%

hace1 Influences zebrafish cardiac development via ROS‐dependent mechanisms

Razaghi

Steele

Prykhozhij

et al. 2017

Developmental Dynamics

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“…Disturbances of the cytoskeletal organisation in myocytes during embryonal development may be responsible for the cardiovascular malformations observed in patients with NF1 microdeletions. This postulate was reinforced by the findings of Venturin et al (2014) who showed that in zebrafish, ADAP2 is required for normal cardiac morphogenesis.…”

Section: Co-deleted Genes With the Potential To Influence The Clinicamentioning

confidence: 82%

“…This conclusion is drawn from the observation that ADAP2 is highly expressed during early stages of heart development in both mouse and human (Venturin et al 2005, 2014). In zebrafish, ADAP2 loss of function leads to circulatory deficiencies and heart shape defects or defective valvulogenesis (Venturin et al 2014). The ADAP 2-encoded protein acts as a GTPase-activating protein (GAP) of the ADP-ribosylation factor 6 (ARF6), a small GTPase involved in actin cytoskeleton remodelling.…”

Section: Co-deleted Genes With the Potential To Influence The Clinicamentioning

confidence: 99%

Emerging genotype–phenotype relationships in patients with large NF1 deletions

2017

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The most frequent recurring mutations in neurofibromatosis type 1 (NF1) are large deletions encompassing the NF1 gene and its flanking regions (NF1 microdeletions). The majority of these deletions encompass 1.4-Mb and are associated with the loss of 14 protein-coding genes and four microRNA genes. Patients with germline type-1 NF1 microdeletions frequently exhibit dysmorphic facial features, overgrowth/tall-for-age stature, significant delay in cognitive development, large hands and feet, hyperflexibility of joints and muscular hypotonia. Such patients also display significantly more cardiovascular anomalies as compared with patients without large deletions and often exhibit increased numbers of subcutaneous, plexiform and spinal neurofibromas as compared with the general NF1 population. Further, an extremely high burden of internal neurofibromas, characterised by >3000 ml tumour volume, is encountered significantly, more frequently, in non-mosaic NF1 microdeletion patients than in NF1 patients lacking such deletions. NF1 microdeletion patients also have an increased risk of malignant peripheral nerve sheath tumours (MPNSTs); their lifetime MPNST risk is 16–26%, rather higher than that of NF1 patients with intragenic NF1 mutations (8–13%). NF1 microdeletion patients, therefore, represent a high-risk group for the development of MPNSTs, tumours which are very aggressive and difficult to treat. Co-deletion of the SUZ12 gene in addition to NF1 further increases the MPNST risk in NF1 microdeletion patients. Here, we summarise current knowledge about genotype–phenotype relationships in NF1 microdeletion patients and discuss the potential role of the genes located within the NF1 microdeletion interval whose haploinsufficiency may contribute to the more severe clinical phenotype.

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“…While these data potentially exclude other members from having any role in regulating the interferon response, it should be kept in mind that the RNAi screening study did not validate the silencing efficiency and on-target specificity of the siRNAs used against other members of the ArfGAP family. Other known functions of ADAP2 include regulation of heart development and stabilization of microtubules (66,70,71). Collectively, all the evidence provides an increased appreciation of the roles of ArfGAP family proteins in host-pathogen interactions.…”

Section: Discussionmentioning

confidence: 91%

ArfGAP Domain-Containing Protein 2 (ADAP2) Integrates Upstream and Downstream Modules of RIG-I Signaling and Facilitates Type I Interferon Production

Bist

Kim

Pulloor

et al. 2017

Molecular and Cellular Biology

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Transcription of type I interferon genes during RNA virus infection requires signal communication between several pattern recognition receptor (PRR)-adaptor complexes located at distinct subcellular membranous compartments and a central cytoplasmic TBK1-interferon regulatory factor 3 (IRF3) kinase-transcription factor module. However, how the cell integrates signal transduction through spatially distinct modules of antiviral signaling pathways is less defined. RIG-I is a major cytosolic PRR involved in the control of several RNA viruses. Here we identify ArfGAP domain-containing protein 2 (ADAP2) as a key novel scaffolding protein that integrates different modules of the RIG-I pathway, located at distinct subcellular locations, and mediates cellular antiviral type I interferon production. ADAP2 served to bridge the mitochondrial membrane-bound upstream RIG-I adaptor MAVS and the downstream cytosolic complex of NEMO (regulatory subunit of TBK1), TBK1, and IRF3, leading to IRF3 phosphorylation. Furthermore, independently, ADAP2 also functioned as a major orchestrator of the interaction of TBK1 with NEMO and IRF3. Mutational and cell-free reconstituted RIG-I signaling assay-based analyses identified that the ArfGAP domain of ADAP2 mediates the interferon response. TRAF3 acted as a trigger for ADAP2 to recruit RIG-I pathway component proteins into a single macromolecular complex. This study provides important novel insights into the assembly and integration of different modules of antiviral signaling cascades.

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ADAP2in heart development: a candidate gene for the occurrence of cardiovascular malformations in NF1 microdeletion syndrome

Abstract: 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.

Cited by 29 publications

References 31 publications

hace1 Influences zebrafish cardiac development via ROS‐dependent mechanisms

hace1 Influences zebrafish cardiac development via ROS‐dependent mechanisms

Emerging genotype–phenotype relationships in patients with large NF1 deletions

ArfGAP Domain-Containing Protein 2 (ADAP2) Integrates Upstream and Downstream Modules of RIG-I Signaling and Facilitates Type I Interferon Production

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