# High-throughput discovery of disease-associated ion channel variants

> **NIH NIH R35** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $437,500

## Abstract

PROJECT SUMMARY
 Ion channels pass charged ions through lipid membranes in a regulated manner. Ion channels
play major roles in regulating electrically excitable tissues, sensing and responding to the
environment, and maintaining cell homeostasis. Over 70 ion channels have been linked to Mendelian
“channelopathy” disorders, affecting a diverse set of organ systems. As genetic testing and genomic
medicine become prominent, an important challenge is to understand the spectrum of which
mutations in ion channel genes cause disease. Unfortunately, a large fraction of variants are currently
annotated as “Variants of Uncertain Significance,” which limits the effectiveness and potential of
genomic medicine.
 This proposal seeks to decipher which variants in channelopathy genes cause disease. We will
first use large biobank datasets with linked genome sequencing and phenotype data. We will examine
associations between genetic variants in 76 channelopathy genes and relevant disease phenotypes.
Using control pathogenic variants, we will first determine which gene-phenotype pairs are associated
in biobank datasets, then discover novel candidate disease-associated variants that are present in
carriers with relevant disease phenotypes. Next, we will use high-throughput automated patch
clamping to study hundreds of variants in ion channel genes. Our initial focus will be 5 key ion
channel genes that span a range of ion types and organ systems, as well as selected variants from
the biobank genetic analyses. Next, we will perform deep mutational scans (a comprehensive
mutational study) of every mutation in selected ion channel genes, starting with GABRA1, a ligand-
gated ion channel gene (receptor) involved in GABA sensing and linked to seizure disorders. We will
generate all possible mutations with degenerate mutagenesis reactions, integrate the mutation library
into cells, then measure each mutation's impact on cell surface trafficking and channel function using
high-throughput sequencing. Finally, we will integrate these patient and in vitro functional datasets to
learn fundamental features of ion channel biology and disease. Through an analysis of the 2D and 3D
protein structures, we will decipher protein mutational hotspots. From an analysis of mutational
impacts from homologous genes I will determine whether mutation information can be ported to
homologous genes. Finally, we will integrate variant data into the American College of Medical
Genetics classification framework to clinically reclassify variants. Overall, these experiments have
great potential to help resolve the VUS problem for ion channels and decipher novel ion channel
biology.

## Key facts

- **NIH application ID:** 10883709
- **Project number:** 5R35GM150465-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Andrew M. Glazer
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $437,500
- **Award type:** 5
- **Project period:** 2023-07-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883709

## Citation

> US National Institutes of Health, RePORTER application 10883709, High-throughput discovery of disease-associated ion channel variants (5R35GM150465-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10883709. Licensed CC0.

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