# CLINICAL, GENETIC, AND CELLULAR CONSEQUENCES OF MUTATIONS IN NA,K-ATPASE ATP1A3

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $717,112

## Abstract

Summary: The neurological importance of the gene for the neuronal alpha3 subunit of the Na/K pump,
ATP1A3, is underscored by the severity and range of symptoms produced by its missense mutations: motor,
cognitive, and psychological. This project uses an integrated interdisciplinary approach. It includes
phenotyping on patients with input on new phenotypes and mechanistic factors. Because new phenotypes
are being discovered incrementally, a gene-first search for variants, phenotypes and risk factors in databases
linked to clinical data should accelerate that. Variants need to be validated, so there will be laboratory tests of
pathogenicity and mechanism, and FDA-approved drugs will be tested for rescue. The purpose is to generate
a comprehensive natural history of symptoms and progression needed for future clinical trials, and preclinical
data for potential treatments. With ATP1A3 there is an extraordinary range of symptoms including severe
infantile manifestations, but the focus here is on the syndromes that manifest in youth and adults: still with a
heavy burden, but perhaps also with more immediate hope for treatments that improve the quality of life.
 We have found that the breadth of symptoms from impaired ATP1A3 activity includes cardiac
rhythmogenesis, and in the brain, we have found patients with focal atrophy and others with only reduced
metabolism by MRI, where there is hope of restoring function. Moreover, ATP1A3 disease overlaps with many
neurologic syndromes, including but not limited to autism, dystonia, parkinsonism, psychiatric disease, and
epilepsy. We anticipate that the results of the proposed work will also point to how Na,K-ATPase dysfunction
contributes to these more common diseases.
 Our goal now is towards a treatment by refining our understanding of ATP1A3 mutation phenotype
diversity and mechanisms. The aims are as follows: Aim 1) Expand the breadth and reach of ATP1A3
phenotyping, using diagnostic tools to detect ATP1A3-related disease and measure changes over time,
necessary for designing treatment trials. Aim 2) Assess ATP1A3 mutations as both causative and risk factors
for disabling diseases by using a genotype-first approach to search existing large population and disease-
specific sequence databases for ATP1A3 variants and correlate these with phenotypic data from linked
electronic health records (EHR) or disease specific phenotype data. Because ATP1A3 mutations are almost
entirely missense and heterozygous, the damaged protein must have to be present, leading to Aim 3):
Investigate multiple mutations from patients for protein misfolding in rigorously comparable isogenic cell
lines. This will test the hypothesis that different symptom clusters have a basis in the cell’s responses to
misfolding: adaptation or apoptosis. For mutations that do misfold, test FDA-approved and new misfolding
corrector drugs for efficacy. In perspective, both longitudinal phenotyping and knowledge of mutant protein
function will be essenti...

## Key facts

- **NIH application ID:** 10297670
- **Project number:** 2R01NS058949-11
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Allison Brashear
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $717,112
- **Award type:** 2
- **Project period:** 2008-04-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10297670

## Citation

> US National Institutes of Health, RePORTER application 10297670, CLINICAL, GENETIC, AND CELLULAR CONSEQUENCES OF MUTATIONS IN NA,K-ATPASE ATP1A3 (2R01NS058949-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10297670. Licensed CC0.

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