# Gaining insights: the effects of the RMK gain-of-function mutations on brain development and neurodevelopmental disorders

> **NIH NIH R01** · STANFORD UNIVERSITY · 2022 · $544,791

## Abstract

Project Summary/Abstract
Rare genetic disorders are a major cause of human morbidity, frequently affect brain development and cause
neurodevelopmental disorders. Here, we propose using Noonan syndrome (NS, 1:2000) as a human model
system to provide critical data on the effects of Ras/mitogen-activated protein kinase (RMK)-genetic alterations
on the human brain's complex systems-level biology. Three lines of evidence support using NS as a human
model system: 1) NS is caused by autosomal dominant mutations of high penetrance in specific genes
compared to idiopathic neurodevelopmental disorders genetics of common variance, 2) NS has a larger impact
on brain development and thus larger effect sizes than idiopathic neurodevelopmental disorders, 3) NS is
associated with increased risk for neurodevelopmental disorders such as attention abilities, learning
disabilities, and autism spectrum symptoms.
Our lab has recently observed the effect of NS mutations in the PTPN11 gene on human brain structure,
specifically the striatum, and brain function, specifically frontostriatal connectivity. However, there is limited
data available on the effect of other NS mutations, RAF1 and SOS1, on the developing brain. To address this
limitation, we propose determining whether three major NS disease genes RAF1, PTPN11, and SOS1
mutations, are associated with striatal alteration in a gradient of severity. To provide critical data on the
relationships between PTPN11 genetic variance and brain development, we will test whether PTPN11
pathogenic variants are associated with altered brain development. Finally, we will test whether whole-brain
connectivity can predict attention abilities in NS. This aim will provide a neuromarker for attention abilities
(specifically inhibition) in NS.
We will perform "deep phenotyping" - imaging studies of the striatum (volume, cellular density, seed-based
functional connectivity) and the whole brain (surface area, cortical thickness, white matter, cortical myelin
content, and whole-brain functional connectivity) and assess attention (inhibition) in children (7-16 years of
age) with RAF1 (n=30), PTPN11 (n=45), and SOS1 (n=30) mutations, and compare them to typically
developing controls (n=45). Two innovative aspects of the proposed work are using restriction spectrum
imaging (RSI) to map the RMK pathway upregulation effect on the striatum cellular density. Second, we will
assess the effect of RAF1 mutations on brain development for the first time.
Defining the relationships between the brain and Noonan's genetics will accelerate the use of genetic testing to
inform prognosis and treatments in NS. Further, describing these relationships will provide critical data on the
role of the RMK in brain development.

## Key facts

- **NIH application ID:** 10420859
- **Project number:** 1R01HD108684-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Tamar Green
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $544,791
- **Award type:** 1
- **Project period:** 2022-08-21 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10420859

## Citation

> US National Institutes of Health, RePORTER application 10420859, Gaining insights: the effects of the RMK gain-of-function mutations on brain development and neurodevelopmental disorders (1R01HD108684-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10420859. Licensed CC0.

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