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

TitleBICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms.
Publication TypeJournal Article
Year of Publication2020
AuthorsBarish, S, Barakat, TStefan, Michel, BC, Mashtalir, N, Phillips, JB, Valencia, AM, Ugur, B, Wegner, J, Scott, TM, Bostwick, B, Murdock, DR, Dai, H, Perenthaler, E, Nikoncuk, A, van Slegtenhorst, M, Brooks, AS, Keren, B, Nava, C, Mignot, C, Douglas, J, Rodan, L, Nowak, C, Ellard, S, Stals, K, Lynch, SAnn, Faoucher, M, Lesca, G, Edery, P, Engleman, KL, Zhou, D, Thiffault, I, Herriges, J, Gass, J, Louie, RJ, Stolerman, E, Washington, C, Vetrini, F, Otsubo, A, Pratt, VM, Conboy, E, Treat, K, Shannon, N, Camacho, J, Wakeling, E, Yuan, B, Chen, C-A, Rosenfeld, JA, Westerfield, M, Wangler, M, Yamamoto, S, Kadoch, C, Scott, DA, Bellen, HJ
Corporate AuthorsUndiagnosed Diseases Network
JournalAm J Hum Genet
Date Published2020 12 03
KeywordsAdolescent, Animals, Child, Child, Preschool, Chromosomal Proteins, Non-Histone, Developmental Disabilities, Drosophila melanogaster, Drosophila Proteins, Female, Genes, Dominant, Genetic Variation, Haploinsufficiency, Humans, Infant, Male, Microscopy, Confocal, Mutation, Missense, Neuroglia, Neurons, Phenotype, Protein Binding, Tumor Suppressor Proteins, Zebrafish, Zebrafish Proteins

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-of-function, 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.

Alternate JournalAm J Hum Genet
PubMed ID33232675
PubMed Central IDPMC7820627
Grant ListR24 OD022005 / OD / NIH HHS / United States
U01 HG007709 / HG / NHGRI NIH HHS / United States
U54 NS093793 / NS / NINDS NIH HHS / United States

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