Background: Bardet-Biedl Syndrome (BBS) and Alström Syndrome are two pleiotropic ciliopathies with significant phenotypic overlap between them across many tissues. Although BBS and Alström genes are necessary for the proper function of primary cilia, their role in defects across multiple organ systems is unclear.
Methods: To provide insight into the pathways underlying BBS and Alström phenotypes, we carried out whole organism transcriptome analysis by RNA sequencing in established zebrafish models of the syndromes.
Results: We analyzed all genes that were significantly differentially expressed and found enrichment of phenotypically significant pathways in both models. These included multiple pathways shared between the two disease models as well as those unique to each model. Notably, we identified significant downregulation of genes in pathways relevant to visual system deficits and obesity in both disorders, consistent with those shared phenotypes. In contrast, neuronal pathways were significantly downregulated only in the BBS model but not in the Alström model. Our observations also suggested an important role for G-protein couple receptor and calcium signaling defects in both models.
Discussion: Pathway network analyses of both models indicate that visual system defects may be driven by genetic mechanisms independent of other phenotypes whereas the majority of other phenotypes are a result of genetic players that contribute to multiple pathways simultaneously. Additionally, examination of genes differentially expressed in opposing directions between the two models suggest a deficit in pancreatic function in the Alström model, that is not present in the BBS model.
Conclusions: These findings provide important novel insight into shared and divergent phenotypes between two similar but distinct genetic syndromes.