Abstract
BackgroundBardet-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.MethodsTo 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.ResultsWe 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.DiscussionPathway 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.ConclusionsThese findings provide important novel insight into shared and divergent phenotypes between two similar but distinct genetic syndromes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2679-1) contains supplementary material, which is available to authorized users.
Highlights
Bardet-Biedl Syndrome (BBS) and Alström Syndrome are two pleiotropic ciliopathies with significant phenotypic overlap between them across many tissues
To fully capture all organ systems that may be impacted by disruption of either bbs1 or alms1, we isolated total RNA from whole zebrafish at 48 hpf, a time point at which most organ systems have developed and begin to be functional
MO-driven knockdown at 48 hpf was verified by western blot (Additional file 1: Figure S1.) RNA from each sample was sequenced to a depth of ~110 million reads with 91–100 million reads aligned to the zebrafish genome
Summary
Bardet-Biedl Syndrome (BBS) and Alström Syndrome are two pleiotropic ciliopathies with significant phenotypic overlap between them across many tissues. BBS and Alström genes are necessary for the proper function of primary cilia, their role in defects across multiple organ systems is unclear. Deciphering the underlying molecular etiology of such diseases can be difficult due to the complexity of interpreting the role of a single gene in multiple disparate cell types. This complexity remains even for syndromes in which the subcellular defect is relatively well understood. Bardet-Biedl Syndrome (BBS) and Alström Syndrome represent pleiotropic syndromes with overlapping features, but for which the primary molecular defects underlying those features are not well understood
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