Mutations in SMARCB1 and in other Coffin\u2013Siris syndrome genes lead to various brain midline defects

Jörg Schaper,Ulrike A Nuber,Linda K Rey,Krzysztof Szczaluba,Alina Filatova,Maja Hempel,Marion B Lechler,Dagmar Wieczorek,Gijs W E Santen,Renata Posmyk

doi:10.1038/s41467-019-10849-y

Abstract

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.

Highlights

Mutations in genes encoding components of BAF (BRG1/BRM-associated factor) chromatin remodeling complexes cause neurodevelopmental disorders and tumors
One of the disorders caused by mutations in BAF complex component genes is Coffin–Siris syndrome (CSS), a congenital malformation syndrome characterized by severe developmental delay affecting motor and intellectual functions, growth impairment, hypotonia, a distinct facial appearance with coarse features, feeding difficulties in infancy, and hypoplastic to absent fifth distal phalanges, fingernails and toenails[5]
A particular heterozygous SMARCB1 mutation has been described in individuals with severe intellectual disability (ID) and choroid plexus hyperplasia (CPH) and we refer to this condition as SMARCB1-related IDCPH11

Summary

Introduction

Mutations in genes encoding components of BAF (BRG1/BRM-associated factor) chromatin remodeling complexes cause neurodevelopmental disorders and tumors. We generated mice with a heterozygous nervous system-specific partial loss-offunction mutation in a BAF core component gene, Smarcb[1] These Smarcb[1] mutant mice show various brain midline abnormalities that are 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). Mutations in genes encoding components of the ATPdependent chromatin remodeling BAF complex (mammalian SWI/SNF complex) are found in two distinct disease types: intellectual disability (ID)/neurodevelopmental disorders and tumors. A particular heterozygous SMARCB1 mutation has been described in individuals with severe ID and choroid plexus hyperplasia (CPH) and we refer to this condition as SMARCB1-related IDCPH11 It remains unresolved how alterations in BAF complex genes lead to the specific developmental brain defects seen in affected individuals. Based on our results and on the review of individuals with SMARCB1 mutations in the literature, we suggest that the development of ID/neurodevelopmental disorders or malignant tumors could depend on a transcriptional compensation by the second intact SMARCB1 allele

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Results

Conclusion