# Characterizing patient-specific TBR1 mutations: Understanding a master regulator of autism risk.

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $499,244

## Abstract

PROJECT SUMMARY/ABSTRACT
 Autism spectrum disorder (ASD) is a common neurodevelopmental disorder characterized by impaired
social communication and restricted, repetitive behaviors. As of now, there are limited effective therapies to
help individuals manage the core symptoms of ASD. The diversity of genetic factors underlying ASD risk
highlights the need to shift our focus from one-size fits all therapeutics to more tailored, individualized therapies.
Recently, next-generation sequencing (NGS) has enabled researchers to identify de novo (newly appearing in
the child) loss of function mutations in many important brain development genes, including genes with in
multiple mutations in unrelated children. These findings provide strong evidence for recurrently mutated genes
playing a significant role in ASD risk and indicate that heterozygous disruption of a single gene essential for
brain development is sufficient to cause autism. TBR1, a transcription factor that serves as a `master regulator'
in brain development, is one such gene of particular interest. TBR1 is mutated in ~0.2% of children with ASD,
making it one of the most common risk factors. Computational analyses using biologic network approaches
suggest that, despite the genetic complexity, converging biology at particular developmental windows and
brain regions may be at play in genetic subsets of ASD. Specifically, the co-expression of high confidence risk
genes converge at midfetal stages of cortical development, where TBR1 is thought to play a key role in the
differentiation, migration, and function of deep layer glutamatergic cortical projection neurons. Moreover, it is
now clear that TBR1 also binds to and regulates ~1/3 of other high confidence autism risk genes, making it a
potential `master regulator' of at least one emerging common autism etiology.
 Evaluating the functional consequences of specific mutations represents a critical step in validating and
understanding the causal link between genotype and phenotype and designing rational targeted
therapies/interventions. We hypothesize that loss of a single copy of TBR1 disrupts human cortical
development by altering the TBR1-regulated network required for proper neuronal identity and migration.
Moreover, disrupting TBR1 or its target genes during this critical developmental window of ASD risk define a
common route to ASD. We previously confirmed that de novo mutations severely impacted the localization and
ability of mutant TBR1 proteins to regulate target genes. Here, we will address the current gaps in our
knowledge of how patient-specific TBR1 mutations affect developing neurons by utilizing cutting-edge genome
editing, functional genomics, and complementary models that leverage patient-derived induced pluripotent
stem cells (iPSCs) converted to forebrain-like organoids (Aim 1) and mouse genetics (Aim 2). These studies
will provide an unprecedented view into the consequences of TBR1 patient-specific mutations on neurons
during cor...

## Key facts

- **NIH application ID:** 9929658
- **Project number:** 5R01MH113926-04
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Brian James O'Roak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $499,244
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9929658

## Citation

> US National Institutes of Health, RePORTER application 9929658, Characterizing patient-specific TBR1 mutations: Understanding a master regulator of autism risk. (5R01MH113926-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9929658. Licensed CC0.

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