# Role of Kdm5c dosage in mouse neural development

> **NIH NIH R03** · UNIVERSITY OF WASHINGTON · 2021 · $77,750

## Abstract

Project Summary/Abstract
Individuals with a supernumerary X chromosome such as those with Klinefelter syndrome (XXY) or Triple X
syndrome (XXX) often have congenital abnormalities that include reduced neurological function. The presence
of extra copies of the X chromosome results in extra copies of genes that escape X inactivation. Thus, abnormally
high dosage of escape genes is an attractive target for the causation of phenotypes seen in common
supernumerary X syndromes. KDM5C, one of the genes that escapes X inactivation, represents a particularly
attractive candidate because it is a dosage-sensitive master regulator important for promoter and enhancer
regulation and neurological function. Indeed, patients with deletion or duplication of the gene have intellectual
disability.
To address the role of Kdm5c over expression we will employ a unique mouse model with skewed X inactivation
and precise over expression of Kdm5c due to insertion of one extra copy of the gene. Other animal models of
Klinefelter or Triple X syndromes have been reported, however it is impossible to determine the effects of
increased dosage of a particular escape gene in such models since the entire cohort of escape genes is
overexpressed.
It is probable that neurological phenotypes observed in supernumerary X syndromes stem from developmental
defects during embryogenesis. Thus, to determine the effects of Kdm5c over expression on the pathways critical
for neurogenesis we use a novel mouse model which specifically over expresses Kdm5c and monitor in vivo
genetic and epigenetic changes genome-wide during neural development at critical time points associated with
neurogenesis in the embryo. Gene expression changes and epigenetic changes will be integrated to identify and
map genes and controlling elements affected by over expression of Kdm5c.
Our goals are to determine whether gene expression and epigenetic modifications are dysregulated during
neurodevelopment in embryos where Kdm5c is over expressed. Our comprehensive in vivo approaches will
provide new insights in understanding the role of escape gene dosage in relevant neurological phenotypes
manifested in common X chromosome aneuploidy syndromes.

## Key facts

- **NIH application ID:** 10105159
- **Project number:** 1R03HD103965-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** JOEL Bradford BERLETCH
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $77,750
- **Award type:** 1
- **Project period:** 2020-11-23 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10105159

## Citation

> US National Institutes of Health, RePORTER application 10105159, Role of Kdm5c dosage in mouse neural development (1R03HD103965-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10105159. Licensed CC0.

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