Connecting craniofacial malformations with neural crest splicing defects by defining the role of nuclear cyclophilin NKTR

By analysing the genome of patients with a syndrome mainly characterised by global developmental delay and craniofacial malformations, we identified mutations in the Natural Killer cell Triggering Receptor (NKTR) gene. Very little is known about the role of NKTR during cellular and developmental processes. Yet the presence of a domain involved in the splicing of messenger RNA and the existence of overlapping syndromes due to defective splicing in neural crest cells (NCCs) suggest that NKTR might be a novel gene implicated in this class of genetic disorders. NCCs are unique group of cells that originate at the neural tube border and participate to the development of several organs including face structures. Our preliminary observations reveal that: NKTR associates with the spliceosome (i.e. the nuclear region where RNA splicing processes occur), when overexpressed in cells; NKTR expression is regulated by the transcription factor SOX9 during craniofacial development in mouse and zebrafish embryos; NKTR inactivation in zebrafish induces defects in face cartilage formation. Based on these premises, we wish to perform deeper analyses aimed at assessing the biological role of NKTR during splicing processes and craniofacial development. Further, we will apply tailored experimental models such as induced Pluripotent Stem Cell-derived NCCs to model the mutation identified and shed light into the pathogenesis of this novel genetic syndrome.