Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein

Charles Anthony Scott; Autumn N Marsden; Michael R Rebagliati; Qihong Zhang; Xitiz Chamling; Charles C Searby; Lisa M Baye; Val C Sheffield; Diane C Slusarski

doi:10.1371/journal.pgen.1006936

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Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein

Journal article

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Peer reviewed

Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein

Charles Anthony Scott, Autumn N Marsden, Michael R Rebagliati, Qihong Zhang, Xitiz Chamling, Charles C Searby, Lisa M Baye, Val C Sheffield and Diane C Slusarski

PLoS genetics, Vol.13(7), pp.e1006936-e1006936

07/2017

DOI: 10.1371/journal.pgen.1006936

PMCID: PMC5550010

PMID: 28753627

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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.

Abnormalities, Multiple - metabolism

Abnormalities, Multiple - pathology

Uterine Diseases - metabolism

Bardet-Biedl Syndrome - metabolism

Humans

Uterine Diseases - pathology

Chromatin Assembly and Disassembly - genetics

Cytoplasm - metabolism

Polydactyly - metabolism

Group II Chaperonins - genetics

Heart Defects, Congenital - genetics

Hydrocolpos - genetics

Bardet-Biedl Syndrome - pathology

Bardet-Biedl Syndrome - genetics

Hydrocolpos - pathology

Active Transport, Cell Nucleus - genetics

Abnormalities, Multiple - genetics

Disease Models, Animal

Cilia - pathology

Polydactyly - genetics

Heart Defects, Congenital - pathology

Hydrocolpos - metabolism

Transcription Factors - biosynthesis

Transcription Factors - genetics

Cilia - metabolism

Protein Transport - genetics

Zebrafish - genetics

Animals

Animals, Genetically Modified - genetics

Uterine Diseases - genetics

Heart Defects, Congenital - metabolism

Mice

Mutation

Chromatin - genetics

Polydactyly - pathology

Details

Title: Subtitle: Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein
Creators: Charles Anthony Scott - Department of Biology, University of Iowa, Iowa City, Iowa, United States of America
Autumn N Marsden - Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, Iowa, United States of America
Michael R Rebagliati - Department of Biology, University of Iowa, Iowa City, Iowa, United States of America
Qihong Zhang - Department of Pediatrics and Ophthalmology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Xitiz Chamling - Department of Pediatrics and Ophthalmology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Charles C Searby - Department of Pediatrics and Ophthalmology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Lisa M Baye - Department of Biology, University of Iowa, Iowa City, Iowa, United States of America
Val C Sheffield - Wynn Institute for Vision Research University of Iowa, Iowa City, Iowa, United States of America
Diane C Slusarski - Wynn Institute for Vision Research University of Iowa, Iowa City, Iowa, United States of America
Resource Type: Journal article
Publication Details: PLoS genetics, Vol.13(7), pp.e1006936-e1006936
DOI: 10.1371/journal.pgen.1006936
PMID: 28753627
PMCID: PMC5550010
NLM abbreviation: PLoS Genet
ISSN: 1553-7390
eISSN: 1553-7404
Publisher: United States
Grant note: R01 EY011298 / NEI NIH HHS\nR01 NS083543 / NINDS NIH HHS\nP30 EY025580 / NEI NIH HHS
Language: English
Date published: 07/2017
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Biology; Ophthalmology and Visual Sciences
Record Identifier: 9983991961602771

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