# Mechanism of AUTS2-linked neurodevelopmental disorders

> **NIH NIH R01** · PACIFIC NORTHWEST RESEARCH INSTITUTE · 2021 · $460,000

## Abstract

PROJECT SUMMARY / ABSTRACT
Many types of neuropsychiatric conditions have a significant genetic component, although they are generally
thought to involve a mix of interacting genes. However, some disorders can also be driven by rare mutations in
single genetic loci, highlighting genes with basic and pivotal roles in neurodevelopment. One such locus, AUTS2,
was originally discovered as disrupted in a pair of autistic twins. However, AUTS2 mutations have since been
linked to a wide range of neurological disorders, including epilepsy, schizophrenia, bipolar disorder, addictive
behaviors to name a few. This single genetic region is thus implicated in an exceptionally broad range of
neuropsychiatric disorders with profound societal impact. However, the way that AUTS2-region mutations
predispose to these diseases is not well understood. Complicating the genetic picture, most human AUTS2
mutations are genomic rearrangements that could impact the functions of other neighboring genes. Of particular
interest in this regard is WBSCR17, which is linked to AUTS2 in a conserved topographically associating domain
(TAD), suggesting co-regulation of the genes. While Auts2 mouse “knockout” mutations express certain
phenotypes that could be considered parallel to certain neuropsychiatric traits, they have not provided a
compelling model for AUTS2-linked disease. This project is focused on a novel mouse mutation, called 16Gso,
which disrupts the Wbscr17-Auts2 TAD and dysregulates both genes. Despite this complex genetic effect, 16Gso
mutants display morphological, behavioral, and brain structural abnormalities that model human AUTS2
phenotypes strikingly well. We hypothesize that Wbscr17 contributes to 16Gso and AUTS2-linke human
neurological phenotypes by interacting with Auts2 in a basic cellular pathway required for the extension, survival,
and connectivity of neuronal processes in the developing and adult brain. Further we propose that disturbance
of this pathway leaves affected individuals susceptible to a wide range neuropsychiatric disease. This proposal
is focused on addressing these hypotheses by defining the contributions of Wbscr17 to 16Gso phenotypes, and
the genetic interactions between Wbscr17 and Auts2. We will investigate the cellular functions regulated by the
two loci in a cellular model, and define the regulatory mechanisms that control these linked genes. Together
these data will provide novel explanations for genotype:phenotype correlations in a genetic region linked broadly
to susceptibilities to human neurological disease.

## Key facts

- **NIH application ID:** 10191048
- **Project number:** 5R01MH114600-06
- **Recipient organization:** PACIFIC NORTHWEST RESEARCH INSTITUTE
- **Principal Investigator:** LISA STUBBS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $460,000
- **Award type:** 5
- **Project period:** 2020-07-16 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10191048

## Citation

> US National Institutes of Health, RePORTER application 10191048, Mechanism of AUTS2-linked neurodevelopmental disorders (5R01MH114600-06). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10191048. Licensed CC0.

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