👤 Fanny Laffargue

Tetralogy of Fallot (TOF) aetiologies remain largely unknown. Although syndromes with genetic cause have been involved, non-syndromic TOF are not completely elucidated, with a genetic diagnosis in less than 20% of the cases. HEY2 is a basic helix-loop-helix (bHLH) repressive transcription factor implicated in cardiac development. In this study, we identify a novel heterozygous missense variant in HEY2 gene segregating within a family presenting with non-syndromic TOF with autosomal dominant transmission. The identified variation c.171 G > C p.(Glu57Asp) was tested through gene reporter assay, revealing a complete disruption of HEY2 repressive activity. These results suggest that HEY2 is a novel gene implicated in the pathogenesis of Tetralogy of Fallot, expanding the genetic spectrum of this congenital heart defect and reinforcing the role of monogenic contributions in non-syndromic TOF. Show less

Cells subjected to stress situations mobilize specific membranes and proteins to initiate autophagy. Phosphatidylinositol-3-phosphate (PI3P), a crucial lipid in membrane dynamics, is known to be essential in this context. In addition to nutriments deprivation, autophagy is also triggered by fluid-flow induced shear stress in epithelial cells, and this specific autophagic response depends on primary cilium (PC) signaling and leads to cell size regulation. Here we report that PI3KC2α, required for ciliogenesis and PC functions, promotes the synthesis of a local pool of PI3P upon shear stress. We show that PI3KC2α depletion in cells subjected to shear stress abolishes ciliogenesis as well as the autophagy and related cell size regulation. We finally show that PI3KC2α and VPS34, the two main enzymes responsible for PI3P synthesis, have different roles during autophagy, depending on the type of cellular stress: while VPS34 is clearly required for starvation-induced autophagy, PI3KC2α participates only in shear stress-dependent autophagy. Show less