# Proteogenetics of Autism Spectrum Disorders

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $637,920

## Abstract

PROJECT SUMMARY/ ABSTRACT
The goal of the proposed research is to use proteomics on samples from patient-derived cells with defined
disease genotypes to identify the disrupted molecular pathways that underpin phenotypes of autism spectrum
disorder (ASD). Family history and twin studies suggest that, in at least some cases, these disorders share
genetic roots, but the degree to which environmental and genetic factors account for individual differences within
the spectrum is currently unknown. The possibility that there is a genetic antecedent to the onset of ASD
stimulated GWAS studies, but these studies were only able to identify genetic risk factors and not specific
causative genes. To gain an understanding of the underlying molecular mechanisms associated with ASD, we
will use human induced pluripotent stem cells (hiPSC) from patients with diseases on the autism spectrum. We
have been reprogrammed fibroblasts from these patients and differentiated them into cells to create organoids,
thus allowing the proteomic study in human diseases that were previously unobtainable (e.g. brain diseases). In
this study, we will use large-scale proteomics combined with single cell proteomics to identify protein changes
in individual cells of two genotypes on the autism spectrum. Patients suffering from the monogenetic disease
Rett Syndrome (RTT) exhibit clinical phenotypes that mirror elements of ASD. We have fibroblasts that contain
the different mutations in the gene MECP2 that cause RTT. We also have cells that contain the copy number
variant CNV 16p11.2, a genetic variant on the autism spectrum. The molecular changes underpinning the
development of ASD are poorly understood, but patient-derived cerebral organoids recapitulate molecular and
morphological changes by gene dosage changes from CNV 16p11.2. We propose to use powerful mass
spectrometry multiplexing technologies (Tandem Mass Tags – TMT) to measure commonalities and differences
in proteome and phosphoproteome encoded by these genotypes. In addition, electrophysiology measurements
will be combined with single cell proteomics to measure protein changes in neurons with electrophysiology
disrupted by these genetic changes.

## Key facts

- **NIH application ID:** 10487554
- **Project number:** 5R01MH100175-09
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Alysson R. Muotri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $637,920
- **Award type:** 5
- **Project period:** 2013-08-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487554

## Citation

> US National Institutes of Health, RePORTER application 10487554, Proteogenetics of Autism Spectrum Disorders (5R01MH100175-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10487554. Licensed CC0.

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