# MOLECULAR MECHANISMS UNDERLYING INTELLECTUAL DISABILITY CAUSED BY MUTATIONS IN THE CHROMATIN MODIFIER KDM5C

> **NIH NIH P50** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2021 · $166,667

## Abstract

PROJECT SUMMARY/ABSTRACT – RESEARCH PROJECT 
Mutations in the gene encoding the transcriptional regulator lysine demethylase 5C (KDM5C) are found in 
patients with intellectual disability (ID). While the direct link between loss of function mutations in KDM5C and 
ID is clear, how KDM5C functions to mediate critical neuronal processes, and therefore the consequence of 
mutations for mechanisms of IDD, remains unknown. The goal of this proposal is to understand the 
relationship between KDM5C-regulated gene expression programs and the occurrence of ID and additional 
comorbid features that are observed in patients. We will achieve this by bringing together a multi-disciplinary 
research team with expertise in complementary analytical tools and model systems to test two hypotheses. 
Aim 1 tests the hypothesis that the use of human iPSC-derived in vitro cell models of KDM5C-induced ID will 
result in the identification of clinically relevant gene expression changes and neuronal functional deficits. One 
key model system we will use is iPSC-derived cerebral organoids, which recapitulate structural and molecular 
aspects of fetal brain development and are a critical research tool used to define the underlying cause(s) of 
neurodevelopmental disorders. Indeed, molecular and cellular studies using in vitro organoid systems allow us 
to carry out studies in a human cell context that would simply not be possible in vivo. iPSCs and organoids will 
be generated from two sources: (1) Cells from patients with KDM5C-induced ID from a newly recruited cohort 
of individuals from which we are generating a genotype-phenotype database; (2) CRISPR-Cas9-mediated 
gene editing to generate a KDM5C null allele and a published ID allele (KDM5CA388P) that lacks histone 
demethylase activity using existing iPSC lines generated from typically developing controls. We will use this 
system to combine morphological, functional and multi-OMICS approaches to define the impact of patient- 
associated mutations in KDM5C. Aim 2 tests the hypothesis that the regulation of translation efficiency in 
neurons by the fly homolog of KDM5C is conserved in mammalian systems and that this function is important 
for cognition. Here we take advantage of fly and mouse animal model systems, both as discovery tools and to 
test hypotheses regarding possible contributors to the cognitive effects of mutations in KDM5C. Because other 
inherited forms of ID have altered translation and correcting this deficit has shown promise in mouse models of 
other ID disorders, we will test whether altered translation similarly plays a key role in a mouse model of 
KDM5C-induced ID. 
 This work is significant because we will define the etiological links between mutations in human KDM5C 
and ID. The proposed studies are technologically innovative in the use of complementary model systems and 
state-of-the-art genomics techniques such as single cell transcriptomics (scRNA-seq). It is also conceptually 
innovative...

## Key facts

- **NIH application ID:** 10239753
- **Project number:** 1P50HD105352-01
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Julie Secombe
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $166,667
- **Award type:** 1
- **Project period:** 2021-07-23 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10239753

## Citation

> US National Institutes of Health, RePORTER application 10239753, MOLECULAR MECHANISMS UNDERLYING INTELLECTUAL DISABILITY CAUSED BY MUTATIONS IN THE CHROMATIN MODIFIER KDM5C (1P50HD105352-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10239753. Licensed CC0.

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