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A Role for the Chromatin-Remodeling Factor BAZ1A in Neurodevelopment
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2016 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 37, no 9, 964-975 p.Article in journal (Refereed) Published
Abstract [en]

Chromatin-remodeling factors are required for a wide range of cellular and biological processes including development and cognition, mainly by regulating gene expression. As these functions would predict, deregulation of chromatin-remodeling factors causes various disease syndromes, including neurodevelopmental disorders. Recent reports have linked mutations in several genes coding for chromatin-remodeling factors to intellectual disability (ID). Here, we used exome sequencing and identified a nonsynonymous de novo mutation in BAZ1A (NM_182648.2:c.4043T > G, p.Phe1348Cys), encoding the ATP-utilizing chromatin assembly and remodeling factor 1 (ACF1), in a patient with unexplained ID. ACF1 has been previously reported to bind to the promoter of the vitamin D receptor (VDR)-regulated genes and suppress their expression. Our results show that the patient displays decreased binding of ACF1 to the promoter of the VDR-regulated gene CYP24A1. Using RNA sequencing, we find that the mutation affects the expression of genes involved in several pathways including vitamin D metabolism, Wnt signaling and synaptic formation. RNA sequencing of BAZ1A knockdown cells and Baz1a knockout mice revealed that BAZ1A carry out distinctive functions in different tissues. We also demonstrate that BAZ1A depletion influence the expression of genes important for nervous system development and function. Our data point to an important role for BAZ1A in neurodevelopment, and highlight a possible link for BAZ1A to ID.

Place, publisher, year, edition, pages
2016. Vol. 37, no 9, 964-975 p.
Keyword [en]
ACF1, BAZ1A, CYP24A1, epilepsy, intellectual disability, neurodevelopment, vitamin D metabolism, Wnt signaling
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-305548DOI: 10.1002/humu.23034ISI: 000382777100015PubMedID: 27328812OAI: oai:DiVA.org:uu-305548DiVA: diva2:1038918
Funder
Swedish Research Council, 521-2014-3093, 521-2012-2639Swedish Cancer Society, 2013/404EU, European Research Council, 282330
Available from: 2016-10-20 Created: 2016-10-19 Last updated: 2016-10-20Bibliographically approved

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Zaghlool, AmmarHalvardson, JonatanZhao, Jin J.Etemadikhah, MitraKalushkova, AntoniaJernberg-Wiklund, HelenaThuresson, Ann-CharlotteFeuk, Lars
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Medicinsk genetik och genomikScience for Life Laboratory, SciLifeLabExperimental and Clinical OncologyDepartment of Immunology, Genetics and Pathology
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