Utilising the zebrafish model organism to study the effect of FLCN in early embryonic development and Genotyping and platelet phenotyping of cases of rare inherited platelet based bleeding disorders

摘要

Birt-Hogg-Dubé syndrome (BHD) (OMIM: #135150) is a rare genodermatosis following a dominant pattern of inheritance. The heritable genetic cause of BHD has been determined as mutations within the gene Folliculin (FLCN). A variable phenotype has been observed in systems modelling loss of function of FLCN, this study therefore intends to take a novel approach to mutational studies by utilising the zebrafish model organism. We exploit the optical benefits of the zebrafish model using imaging analysis of a Fucci transgenic line and in situ hybridisation and are able to suggest a possible functional role of FLCN within cell cycle regulation and morphogenesis in the developing brain.ududPlatelet based bleeding disorders are a rare subset of bleeding diathesis that can incorporate thrombocytopenias and platelet function defects. Both thrombocytopenias and platelet function defects present clinically with symptoms relating to hypocoagulability that often manifest as a variation of bleeding episodes. To date there is a large collection of inherited platelet based bleeding disorders incorporating a spectrum of genes with an elucidated role in platelet development or function. This study aims to progress work in this field by using a whole exome sequencing approach following the Genotyping and Platelet Phenotyping (GAPP) protocol. We focus our efforts on two patients families and determine novel candidate variations as potentially disease causing. These candidate variations offer a starting point for subsequent research which can help produce a novel diagnosis and determine new genes with an involvement in platelet functioning and development.ud