PUBLICATION
Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein
- Authors
- Scott, C.A., Marsden, A.N., Rebagliati, M.R., Zhang, Q., Chamling, X., Searby, C.C., Baye, L.M., Sheffield, V.C., Slusarski, D.C.
- ID
- ZDB-PUB-170729-1
- Date
- 2017
- Source
- PLoS Genetics 13: e1006936 (Journal)
- Registered Authors
- Baye, Lisa, Rebagliati, Michael, Slusarski, Diane C.
- Keywords
- Zebrafish, Heart, Embryos, Cytoplasm, Cilia, 293T cells, Gene expression, Congenital heart defects
- MeSH Terms
-
- Zebrafish/genetics
- Protein Transport/genetics
- Cilia/metabolism
- Cilia/pathology
- Animals, Genetically Modified/genetics
- Mice
- Active Transport, Cell Nucleus/genetics
- Abnormalities, Multiple/genetics*
- Abnormalities, Multiple/metabolism
- Abnormalities, Multiple/pathology
- Uterine Diseases/genetics*
- Uterine Diseases/metabolism
- Uterine Diseases/pathology
- Polydactyly/genetics*
- Polydactyly/metabolism
- Polydactyly/pathology
- Chromatin Assembly and Disassembly/genetics
- Heart Defects, Congenital/genetics*
- Heart Defects, Congenital/metabolism
- Heart Defects, Congenital/pathology
- Humans
- Bardet-Biedl Syndrome/genetics*
- Bardet-Biedl Syndrome/metabolism
- Bardet-Biedl Syndrome/pathology
- Chromatin/genetics
- Mutation
- Animals
- Cytoplasm/metabolism
- Transcription Factors/biosynthesis
- Transcription Factors/genetics*
- Hydrocolpos/genetics*
- Hydrocolpos/metabolism
- Hydrocolpos/pathology
- Disease Models, Animal
- Group II Chaperonins/genetics*
- PubMed
- 28753627 Full text @ PLoS Genet.
Citation
Scott, C.A., Marsden, A.N., Rebagliati, M.R., Zhang, Q., Chamling, X., Searby, C.C., Baye, L.M., Sheffield, V.C., Slusarski, D.C. (2017) Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein. PLoS Genetics. 13:e1006936.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping