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

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

doi:10.1038/s41467-019-10849-y

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

Nat Commun. 2019 Jul 4;10(1):2966. doi: 10.1038/s41467-019-10849-y.

Authors

Affiliations

¹ Stem Cell and Developmental Biology, Technical University Darmstadt, Darmstadt, 64287, Germany.
² Institute of Human Genetics, Medical Faculty, Heinrich Heine University, Düsseldorf, 40225, Germany.
³ Department of Diagnostic and Interventional Radiology, Medical Faculty, Heinrich Heine University, Düsseldorf, 40225, Germany.
⁴ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, 20246, Germany.
⁵ Podlaskie Medical Centre "GENETICS" Bialystok and Department of Perinatology and Obstetrics, Medical University of Bialystok, Bialystok, 15-276, Poland.
⁶ Department of Medical Genetics, Medical University Warsaw, Warsaw, 02-106, Poland.
⁷ Department of Clinical Genetics, Leiden University Medical Center, Leiden, 2333 ZA, Netherlands.
⁸ Stem Cell and Developmental Biology, Technical University Darmstadt, Darmstadt, 64287, Germany. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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
Child
Child, Preschool
Corpus Callosum / cytology
Corpus Callosum / diagnostic imaging
Corpus Callosum / growth & development*
Disease Models, Animal
Embryo, Mammalian
Face / abnormalities*
Face / diagnostic imaging
Female
Hand Deformities, Congenital / diagnostic imaging
Hand Deformities, Congenital / genetics*
Humans
Infant
Intellectual Disability / diagnostic imaging
Intellectual Disability / genetics*
Loss of Function Mutation
Magnetic Resonance Imaging
Male
Mice
Mice, Transgenic
Micrognathism / diagnostic imaging
Micrognathism / genetics*
Neck / abnormalities*
Neck / diagnostic imaging
Neuroglia / pathology
Primary Cell Culture
SMARCB1 Protein / genetics*

Substances

SMARCB1 Protein
SMARCB1 protein, human
Smarcb1 protein, mouse

Supplementary concepts

Coffin-Siris syndrome