header logo image header logo text
Downloads Login
General Information
ZFIN ID: ZDB-PUB-170729-1
Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein
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.
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:
  • Abnormalities, Multiple/genetics*
  • Abnormalities, Multiple/metabolism
  • Abnormalities, Multiple/pathology
  • Active Transport, Cell Nucleus/genetics
  • Animals
  • Animals, Genetically Modified/genetics
  • Bardet-Biedl Syndrome/genetics*
  • Bardet-Biedl Syndrome/metabolism
  • Bardet-Biedl Syndrome/pathology
  • Chromatin/genetics
  • Chromatin Assembly and Disassembly/genetics
  • Cilia/metabolism
  • Cilia/pathology
  • Cytoplasm/metabolism
  • Disease Models, Animal
  • Group II Chaperonins/genetics*
  • Heart Defects, Congenital/genetics*
  • Heart Defects, Congenital/metabolism
  • Heart Defects, Congenital/pathology
  • Humans
  • Hydrocolpos/genetics*
  • Hydrocolpos/metabolism
  • Hydrocolpos/pathology
  • Mice
  • Mutation
  • Polydactyly/genetics*
  • Polydactyly/metabolism
  • Polydactyly/pathology
  • Protein Transport/genetics
  • Transcription Factors/biosynthesis
  • Transcription Factors/genetics*
  • Uterine Diseases/genetics*
  • Uterine Diseases/metabolism
  • Uterine Diseases/pathology
  • Zebrafish/genetics
PubMed: 28753627 Full text @ PLoS Genet.
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.