Claudie Comeau^1,2, Marie-Claude Guyot¹, Mingqin Wang¹, Zoha Kibar^1,2et Jacques L Michaud^1,2

¹Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal,
²Department of Biochemistry and Molecular Medicine University of Montreal

Retinoic acid (RA) is required for the development of several organs, including the brain, eye, heart, and lungs. Both loss and gain of RA signalling disrupt the development of these organs, indicating that its precise regulation is required for appropriate development. RA can bind to retinoic acid receptors (RARs), which are transcription factors that modulate target genes expression. De novo mutations in theRARB gene lead to a severe rare and complex syndrome called PDAC charcaterized mainly by anophthalmia and/or microphthalmia, pulmonary hypoplasia, diaphragmatic hernia and cardiac defects.In total, our group have identified 15 pathogenic variants in RARBin more than 30 patients affected with PDAC. Some of these variants induce gain-of-function (GOF) whereas others act in a dominant-negative (DN) manner in cell-based transcriptional assays. The goal of this project is to use the zebrafish model to study the functional impact of RARB variants in vivo. We found that expression of wild-type human RARB RNA in zebrafish caused microphthalmia, swim bladder defects and curvature of the body axis. The introduction of a non-sense variant (p.K102X) abolished these effects. We are currently testing the impact of putative GOF (p.R269T, p.R387C) and DN (p.M290R, p.L402P, p.S398X) on this RARB activity. We will conduct overexpression assays with these mutants and study the resulting phenotype to further investigate their mode of action. A better understanding of the molecular mechanism of RARβ during development might help develop effective therapeutic strategies through the modulation of the RA signaling.