Return to search

Novel mechanisms of Bardet-Biedl syndrome proteins: implications in blindness and congenital heart disease

Mutations in BBS6 cause two clinically distinct syndromes, Bardet-Biedl syndrome (BBS), a syndrome caused by defects in cilia transport and function, as well as McKusick-Kaufman syndrome, a genetic disorder characterized by congenital heart defects. Congenital heart defects are rare in BBS, and McKusick-Kaufman syndrome patients do not develop retinitis pigmentosa. Therefore, the McKusick-Kaufman syndrome allele may highlight cellular functions of BBS6 distinct from the presently understood functions in the cilia. In support, we find that the McKusick-Kaufman syndrome disease-associated allele, BBS6H84Y; A242S, maintains cilia function. We demonstrate that BBS6 is actively transported between the cytoplasm and nucleus, and that BBS6H84Y; A242S, is defective in this transport. We developed a transgenic zebrafish with inducible bbs6 to identify novel binding partners of BBS6, and we find interaction with the SWI/SNF chromatin remodeling protein Smarcc1a (SMARCC1 in humans). We demonstrate that through this interaction, BBS6 modulates the sub-cellular localization of SMARCC1 and find, by transcriptional profiling, similar transcriptional changes following smarcc1a and bbs6 manipulation. Our work identifies a new function for BBS6 in nuclear-cytoplasmic transport, and provides insight into the disease mechanism underlying the congenital heart defects in McKusick-Kaufman syndrome patients.

Identiferoai:union.ndltd.org:uiowa.edu/oai:ir.uiowa.edu:etd-7326
Date01 August 2017
CreatorsScott, Charles Anthony
ContributorsSlusarski, Diane C.
PublisherUniversity of Iowa
Source SetsUniversity of Iowa
LanguageEnglish
Detected LanguageEnglish
Typedissertation
Formatapplication/pdf
SourceTheses and Dissertations
RightsCopyright © 2017 Charles Anthony Scott

Page generated in 0.0016 seconds