BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms

Abstract

SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-offunction, 2 missense) in the BICRA (BRD4 interacting chromatin remodeling complex-associated protein) gene, also known as GLTSCR1, which encodes a subunit of the non-canonical BAF (ncBAF) complex. These individuals exhibited neurodevelopmental phenotypes that include developmental delay, intellectual disability, autism spectrum disorder, and behavioral abnormalities as well as dysmorphic features. Notably, the majority of individuals lack the fifth digit/nail hypoplasia phenotype, a hallmark of most SSRIDDs. To confirm the role of BICRA in the development of these phenotypes, we performed functional characterization of the zebrafish and Drosophila orthologs of BICRA. In zebrafish, a mutation of bicra that mimics one of the loss-of-function variants leads to craniofacial defects possibly akin to the dysmorphic facial features seen in individuals harboring putatively pathogenic BICRA variants. We further show that Bicra physically binds to other non-canonical ncBAF complex members, including the BRD9/7 ortholog, CG7154, and is the defining member of the ncBAF complex in flies. Like other SWI/SNF complex members, loss of Bicra function in flies acts as a dominant enhancer of position effect variegation but in a more context-specific manner. We conclude that haploinsufficiency of BICRA leads to a unique SSRIDD in humans whose phenotypes overlap with those previously reported.

In vivo analysis reveals that ATP-hydrolysis couples remodeling to SWI/SNF release from chromatin

“…We detected the fly homolog of GLTSCR1 in GFP-BRM IPs from S2 cells ( Figure 4B ). Indeed, a recent study identified and characterized the fly BRM complex that is orthologous to mammalian GBAF/ncBAF ( Barish et al, 2020 ). Thus, although GBAP appears to be mainly expressed in the nervous system, it might contribute to our analysis of BRM dynamics.…”

Sparse dictionary learning recovers pleiotropy from human cell fitness screens

“…BRD7 z 0 3 ncBAF complex + 0 3 cBAF complex + 0.8 3 pBAF complex . The ancestral BRD7/9 protein in Drosophila binds both pBAF and ncBAF (Barish et al, 2020), but gene duplication evolved two specialized mammalian paralogs that exclusively function complex. An unknown interactor, C7orf26, was approximated as a mixture of all three Integrator functions, with the strongest loaded function mapping to the INTS10-13-14 functional module.…”

Case Report: BAF-Opathies/SSRIDDs Due to a de novo ACTL6A Variant, Previously Considered to Be Heart-Hand Syndrome

“…Mutations in genes encoding components of the BAF complex, such as ARID1B, ARID1A, ARID2, SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, DPF2, and BICRA, cause a range of disorders, including syndromic intellectual disability, Coffin-Siris syndrome (CSS), and Nicolaides-Baraitser syndrome (NCBRS) (6,(12)(13)(14)(15)(16)(17)(18). Two terms, "SWI/SNF related intellectual disability disorders" (SSRIDDs) and "BAF-opathies, " have been proposed to represent the full range of these diseases (8,10).…”