# Defining the molecular basis of autism caused by inherited null mutations in BAF53B

> **NIH NIH F31** · STANFORD UNIVERSITY · 2020 · $18,928

## Abstract

ABSTRACT
Autism spectrum disorder (ASD) is a highly prevalent group of neurodevelopmental disorders whose treatment
efficacy is limited by poor understanding of its causal molecular mechanisms. To gain insight into the molecular
basis of autism, we sequenced the genomes of families with recessively inherited autism and identified six
distinct, deleterious mutations in the gene BAF53B, which segregate bi-allelically with the disorder. Since no
other mutations showed this pattern of inheritance, this indicates that BAF53B loss-of-function mutations
cause autism in these patients. Preliminary behavioral testing of Baf53b-/- mice further indicates a conserved
role for this gene in social behaviors. Since BAF53B protein is exclusively expressed in neurons, this suggests
that autism in may arise from defects in neuronal maturation or plasticity. Indeed, preliminary RNA-sequencing
data from Baf53b-/- cortical mouse neurons indicate a specific requirement for Baf53b in activity-dependent
transcriptional regulation. This is consistent with an early study that observed defects in activity-dependent
dendritic outgrowth and aberrant mRNA expression by microarray analysis in Baf53b-/- neurons. The
mechanisms through which Baf53b regulates neuronal transcription are likely to be related to its role as a core
subunit of the neuronal BAF (nBAF) ATP-dependent chromatin remodeling complex. BAF complexes utilize
ATP to regulate genome accessibility and nucleosome turnover, and to evict Polycomb repressive complexes.
Indeed, defects in nBAF genomic targeting have been observed at subsets of genes tested in Baf53b-/- mouse
neurons, leading to the hypothesis that BAF53B loss-of-function may cause autism, in part, through
failures in local chromatin remodeling by the nBAF complex. In line with this, additional BAF subunits
ARID1B, SMARCA2 and BCL11A have been listed as “syndromic” autism genes by SFARI, underscoring a
critical, yet poorly understood function for nBAF in regulating autism-associated molecular pathways. Thus, a
deeper mechanistic understanding how Baf53b and the nBAF complex regulate neuronal gene
expression is warranted.
The proposed study will utilize Baf53b-/- mouse neurons as a model to uncover potential mechanisms through
which BAF53B loss-of-function causes autism in humans. A combination of proteomics and next generation
sequencing will be employed to define Baf53b-dependent nBAF protein interactions and targeting mechanisms
(Specific Aim 1), and to determine which nBAF chromatin remodeling activities are sensitive to Baf53b loss-of-
function (Specific Aim 2). The conclusion of this study will reveal basic insights into gene regulation in
the nervous system and importantly, will highlight potential mechanisms through which disruptions in
the nBAF complex cause autism in humans. Such information is crucial to inform the development of
effective methods to diagnose and treat ASD.

## Key facts

- **NIH application ID:** 9870946
- **Project number:** 5F31MH116588-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Wendy Wenderski
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $18,928
- **Award type:** 5
- **Project period:** 2018-03-09 → 2020-09-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9870946

## Citation

> US National Institutes of Health, RePORTER application 9870946, Defining the molecular basis of autism caused by inherited null mutations in BAF53B (5F31MH116588-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9870946. Licensed CC0.

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