# Integrative functional genomic study of pathways impacted by recurrent autism CNV

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $485,555

## Abstract

SUMMARY
Copy number variants (CNVs) and de novo mutations represent significant risk factors for Autism Spectrum
Disorders (ASD). One of the most frequent CNVs involved in ASD is a deletion or duplication of the
16p11.2
CNV locus, spanning 29 protein-coding genes. Despite the progress in linking 16p11.2 genetic changes with
the phenotypic (macrocephaly and microcephaly) abnormalities in the patients and model organisms, the
specific molecular pathways impacted by this CNV remain unknown. In our recent study we demonstrated that
KCTD13, a gene within the 16p11.2 locus, is co-expressed and physically interacts with Cul3 ubiquitin ligase
primarily during late mid-fetal cortical brain development. This interaction may be crucial for regulating the
levels of a small GTPase RhoA, a major regulator of actin cytoskeleton and cell migration. Based on these
results, we propose the hypothesis that functional impact of the 16p11.2 CNV is manifested through
dysregulation of the RhoA and downstream signaling pathways including neuronal migration, cytoskeletal
dynamics, proliferation and apoptosis. We will test this hypothesis using existing 16p11.2 (Horev, 2011;
Portmann, 2014) and developing new KCTD13 and Cul3 mouse models with CRISPR/Cas9 technology. To
investigate cellular and molecular pathways impacted by the 16p11.2 CNV, we will apply integrative functional
genomics approaches including genome-wide transcriptomic and proteomic profiling of the embryonic and
early postnatal brain tissues. The goal of this project is to develop better understanding of the relationships
between brain size and the 16p11.2 deletion/duplication genotypes, and to determine the detailed cellular and
molecular mechanisms responsible for brain size differences. We will achieve this goal through the following
Specific Aims: (1) Generate KCTD13 and CUL3 mouse models using CRISPR/Cas9 system and characterize
cellular phenotypes in the developing brain; (2) Investigate molecular impact of the 16p11.2 CNV, KCTD13 and
CUL3 mutations to identify dysregulated pathways; (3) Characterize behavioral phenotypes of the developed
mouse models and test pharmacological inhibitors for phenotype reversal. This project will address an
important but yet unresolved question regarding cellular and molecular pathways disrupted by the most
frequent CNV implicated in multiple neurodevelopmental disorders. These pathways may represent high
priority targets for future therapeutic interventions in ASD.

## Key facts

- **NIH application ID:** 9941139
- **Project number:** 5R01MH108528-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** LILIA M IAKOUCHEVA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $485,555
- **Award type:** 5
- **Project period:** 2016-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9941139

## Citation

> US National Institutes of Health, RePORTER application 9941139, Integrative functional genomic study of pathways impacted by recurrent autism CNV (5R01MH108528-05). Retrieved via AI Analytics 2026-08-01 from https://api.ai-analytics.org/grant/nih/9941139. Licensed CC0.

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