# Harnessing post-translational regulation of SHANK3 as a boosting strategy for Phelan-McDermid syndrome

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $536,951

## Abstract

PROJECT SUMMARY
Proper brain development requires precise dosages of genes critical for synapse formation. Alterations of gene
dosage through loss-of-function mutations, such as genomic deletions, or gain of function mutations, such as
genomic duplications, result in approximately 50% change in protein content. This often has devastating
consequences for brain development and function. In one example, dominant, loss-of-function mutations in the
post-synaptic scaffolding protein encoded by the SHANK3 gene causes a severe neurodevelopmental
disorder, Phelan-McDermid syndrome. Individuals with Phelan-McDermid syndrome have moderate to severe
intellectual disability with developmental delays often noted in the first two years of life. There are currently no
targeted therapies for this disorder.
This proposal aims to investigate SHANK3’s post-translational regulation to add fundamental knowledge of
synaptic development and physiology and develop treatment avenues for individuals with SHANK3 mutations.
In this proposal, a combination of biochemistry, behavior and neurophysiology will be utilized to address the
following: 1. Determine if in vivo inhibition of ERK2 rescues molecular and behavioral abnormalities due to
SHANK3 haploinsufficiency. 2. Determine the impact of Casein Kinase inhibition on SHANK3 stability and
function and 3. Identify the proteasomal elements which regulate SHANK3 stability.
The impact of this work will be to understand the dynamic regulation of SHANK3 through post-translational
mechanisms, develop pre-clinical insight into therapeutic treatment avenues for Phelan-McDermid syndrome
and develop a molecular approach for identifying personalized therapies for neurodevelopmental disorders due
to mutations in dosage sensitive genes.

## Key facts

- **NIH application ID:** 10177755
- **Project number:** 1R01NS120980-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** JIMMY L HOLDER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $536,951
- **Award type:** 1
- **Project period:** 2021-06-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10177755

## Citation

> US National Institutes of Health, RePORTER application 10177755, Harnessing post-translational regulation of SHANK3 as a boosting strategy for Phelan-McDermid syndrome (1R01NS120980-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10177755. Licensed CC0.

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