Modeling rare genetic diseases in C. elegans and Zebrafish

In this PhD thesis two different animal models, the invertebrate C. elegans and Zebrafish, where exploited to characterize and get insights in rare genetic diseases. The use of these organisms in the field of medical genetics have been proved to be of great significance in many contexts. First, we employed the nematode C. elegans to characterize two Variants of Uncertain Significance (VUS) found in a patient with a severe neonatal-onset conditions reminiscent of a ciliopathy. Taking advantage of the anatomical similarities between cilia morphology in humans and worms and the easiness in manipulating C. elegans genome, we were able to generate a worm model that helped us elucidate the pathogenicity of these mutations. Our data demonstrated the loss of function effects of the novel variants, while proving the hypomorphic nature of the missense change, and finally allowed to define a novel autosomal recessive form of ciliopathy, contributing to expand the increasing number of this group of inherited ciliopathies. Second, we worked with D. rerio, better known as zebrafish, to study more complex and multisystemic phenotypes, such as Schwannomatosis and Malignant Rhabdoid Tumor (MRT). These diseases are caused by loss of function mutations in the SMARCB1 gene, highly conserved from lower organisms to humans. We were able to generate the KO animals of both paralogues of SMARCB1 in Zebrafish and to characterize their phenotype. These mutants represent useful models to get deeper insights in the pathogenesis of these conditions in humans and, hopefully, to test novel treatments related not only to tumor development but also to pain pathophysiology.