# Models to study heritable and de novo DAND mutations

> **NIH NIH R03** · SOUTHERN ILLINOIS UNIVERSITY CARBONDALE · 2023 · $73,750

## Abstract

Project Summary
DEAF1-associated neurodevelopmental disorder (DAND) is a phenotypic spectrum of features that include
intellectual disability and autism spectrum disorder (ASD). Individuals with DAND have clinical phenotypes that
overlap with other neurodevelopmental disorders including Angelman and Rett syndromes. DAND is caused by
single allelic de novo and bi-allelic heritable mutations in the DEAF1 gene. Our functional studies indicate that
identified de novo mutations disrupt DEAF1 transcriptional activity and suggest that the mutations are dominant
negative. The effects of heritable variants on DEAF1 function remain unclear. This proposal focuses on two
identified DEAF1 variants, p.Q264P (de novo) and p.R226W (heritable). The resultant spectrum disorders of
individuals with heritable and de novo DEAF1 mutations is remarkably quite similar. We hypothesize there is a
common set of altered DEAF1 target genes, caused by the heritable and de novo DEAF1 mutations, that underlie
the pathogenesis of DAND. The innovation of this proposal is the development of new model systems that more
closely represent DAND. The current best model for assessing the effects of decreased DEAF1 activity on
cognitive function is a conditional knockout model. Although the knockout model demonstrates the importance
of DEAF1 expression in learning and memory, it does not mirror the allelic profile of DAND or, more importantly,
account for dominant negative or possible gain-of-function actions of the mutant DEAF1 proteins. We will use
CRISPR/Cas9-mediated genomic engineering to develop p.R227W and p.Q265P (analogous to p.R226W and
p.Q264P in humans) point mutation knock-in mouse models of DAND. Neurobehavioral testing will assess the
effects of mutant DEAF1 proteins on learning and memory. We will also identify transcriptomic changes in
postnatal developing and adult hippocampus. A common set of differentially expressed genes, likely causal to
the cognitive deficits, will be determined by comparing these two models. These models will provide important
insights into DAND, as well as other developmental disorders with overlapping clinical phenotypes.

## Key facts

- **NIH application ID:** 10551868
- **Project number:** 5R03MH128464-02
- **Recipient organization:** SOUTHERN ILLINOIS UNIVERSITY CARBONDALE
- **Principal Investigator:** Philip J. Jensik
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $73,750
- **Award type:** 5
- **Project period:** 2022-01-17 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10551868

## Citation

> US National Institutes of Health, RePORTER application 10551868, Models to study heritable and de novo DAND mutations (5R03MH128464-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10551868. Licensed CC0.

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