BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms.
Adolescent
Animals
Child
Child, Preschool
Chromosomal Proteins, Non-Histone
/ genetics
Developmental Disabilities
/ genetics
Drosophila Proteins
/ genetics
Drosophila melanogaster
Female
Genes, Dominant
Genetic Variation
Haploinsufficiency
Humans
Infant
Male
Microscopy, Confocal
Mutation, Missense
Neuroglia
/ metabolism
Neurons
/ metabolism
Phenotype
Protein Binding
Tumor Suppressor Proteins
/ genetics
Zebrafish
Zebrafish Proteins
/ genetics
BAFopathy
CG11873
Drosophila
GLTSCR1
chromatin
developmental delay
intellectual disability
ncBAF complex
position effect variegation
zebrafish
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
03 12 2020
03 12 2020
Historique:
received:
30
06
2020
accepted:
03
11
2020
pubmed:
25
11
2020
medline:
13
1
2021
entrez:
24
11
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33232675
pii: S0002-9297(20)30400-6
doi: 10.1016/j.ajhg.2020.11.003
pmc: PMC7820627
pii:
doi:
Substances chimiques
BICRA protein, Drosophila
0
BICRA protein, human
0
Chromosomal Proteins, Non-Histone
0
Drosophila Proteins
0
Tumor Suppressor Proteins
0
Zebrafish Proteins
0
bicra protein, zebrafish
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1096-1112Subventions
Organisme : NIH HHS
ID : R24 OD022005
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG007709
Pays : United States
Organisme : NINDS NIH HHS
ID : U54 NS093793
Pays : United States
Informations de copyright
Copyright © 2020 American Society of Human Genetics. All rights reserved.
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