Mutations in SMARCB1 and in other Coffin–Siris syndrome genes lead to various brain midline defects

• Published in: Nature communications Vol. 10; no. 1; pp. 2966 - 14
• Main Authors: Filatova, Alina, Rey, Linda K., Lechler, Marion B., Schaper, Jörg, Hempel, Maja, Posmyk, Renata, Szczaluba, Krzysztof, Santen, Gijs W. E., Wieczorek, Dagmar, Nuber, Ulrike A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04-07-2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 13/51; 14/63; 38/22; 38/77; 38/88; 45/71; 631/136; 631/208/135; 631/378/2571; 64/60; 692/308/1426; Abnormalities; Abnormalities, Multiple - diagnostic imaging; Abnormalities, Multiple - genetics; Agenesis of Corpus Callosum - diagnostic imaging; Agenesis of Corpus Callosum - genetics; Agenesis of Corpus Callosum - pathology; Alleles; Animals; Brain; BRG1 protein; Child; Child, Preschool; Choroid plexus; Chromatin remodeling; Coffin-Siris syndrome; Core loss; Corpus callosum; Corpus Callosum - cytology; Corpus Callosum - diagnostic imaging; Corpus Callosum - growth & development; Disease Models, Animal; Disorders; Embryo, Mammalian; Face - abnormalities; Face - diagnostic imaging; Female; Genes; Hand Deformities, Congenital - diagnostic imaging; Hand Deformities, Congenital - genetics; Humanities and Social Sciences; Humans; Hyperplasia; Infant; Intellectual Disability - diagnostic imaging; Intellectual Disability - genetics; Loss of Function Mutation; Magnetic Resonance Imaging; Male; Mice; Mice, Transgenic; Micrognathism - diagnostic imaging; Micrognathism - genetics; multidisciplinary; Mutation; Neck - abnormalities; Neck - diagnostic imaging; Nervous system; Neurodevelopmental disorders; Neuroglia - pathology; Primary Cell Culture; Science; Science (multidisciplinary); SMARCB1 Protein - genetics; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10849-y

Mutations in genes encoding components of BAF (BRG1/BRM-associated factor) chromatin remodeling complexes cause neurodevelopmental disorders and tumors. The mechanisms leading to the development of these two disease entities alone or in combination remain unclear. We generated mice with a heterozygous nervous system-specific partial loss-of-function mutation in a BAF core component gene,
Smarcb1
. These
Smarcb1
mutant mice show various brain midline abnormalities that are also found in individuals with Coffin–Siris syndrome (CSS) caused by
SMARCB1
,
SMARCE1
, and
ARID1B
mutations and in
SMARCB1
-related intellectual disability (ID) with choroid plexus hyperplasia (CPH). Analyses of the
Smarcb1
mutant animals indicate that one prominent midline abnormality, corpus callosum agenesis, is due to midline glia aberrations. Our results establish a novel role of
Smarcb1
in the development of the brain midline and have important clinical implications for BAF complex-related ID/neurodevelopmental disorders.
Why and how mutations in genes encoding BAF complex components lead to distinct disease entitites remains unresolved. In this study, authors establish the first
Smarcb1
mutant mouse model with multiple brain abnormalities recapitulating human Coffin–Siris syndrome and show that one prominent midline abnormality, corpus callosum agenesis, is due to midline glia aberrations.