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BICRA, a SWI/SNF complex member, is associated with a novel BAFopathy

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posted on 20.04.2020 by Scott Barish, Berrak Ugur, Alfredo valencia, Nazar Mashtalir, Cigall Kadoch, Daryl A. Scott, Michael F. Wangler, Shinya Yamamoto, Hugo J. Bellen
SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare but severe neurodevelopmental disorders that are characterized by developmental disability, hypoplasia of the fifth digit, and coarse facial features. Variants in the members of the SWI/SNF chromatin remodeling complex cause SSRIDDs. Through the Undiagnosed Disease Network (UDN) and GeneMatcher we identified 12 individuals with symptoms similar to CSS, who carries a de novo frameshift allele in the gene BRD4 Interacting Chromatin Remodeling Complex Associated protein (BICRA), a non-canonical member of the SWI/SNF complex, not previously connected to disease. Here we present the first functional characterization of the Drosophila homolog of BICRA, bicra, and correspondingly the first functional characterization the non-canonical SWI/SNF complex in vivo. We show that Bicra binds to other non-canonical SWI/SNF complex members and is broadly expressed in neurons and glia in the nervous system. We demonstrate that, unlike other SWI/SNF complex members, loss of bicra is a dominant enhancer of position effect variegation at telomeres. bicra mutants also exhibit climbing defects at day 1 and live only for one week, both of which can be rescued by the genomic locus. Finally, we show that bicra plays a critical role in glia via RNAi knockdown. Together our data show that BICRA is a SWI/SNF complex member whose loss leads to a novel SSRIDD.

Funding

Center for functional analysis of human UDN gene homologs in Drosophila and zebrafish

National Institute of Neurological Disorders and Stroke

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2318B

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