Feinberg
Northwestern Medicine | Northwestern University | Faculty Profiles

News Center

  • Categories
    • Campus News
    • Disease Discoveries
    • Clinical Breakthroughs
    • Education News
    • Scientific Advances
  • Press Releases
  • Media Coverage
  • Podcasts
  • Editor’s Picks
    • COVID-19
    • Cardiology
    • Cancer
    • Neurology and Neuroscience
    • Aging and Longevity
    • Artificial Intelligence in Medicine
  • News Archives
  • About Us
    • Media Contact
    • Share Your News
    • News Feeds
    • Social Media
    • Contact Us
Menu
  • Categories
    • Campus News
    • Disease Discoveries
    • Clinical Breakthroughs
    • Education News
    • Scientific Advances
  • Press Releases
  • Media Coverage
  • Podcasts
  • Editor’s Picks
    • COVID-19
    • Cardiology
    • Cancer
    • Neurology and Neuroscience
    • Aging and Longevity
    • Artificial Intelligence in Medicine
  • News Archives
  • About Us
    • Media Contact
    • Share Your News
    • News Feeds
    • Social Media
    • Contact Us
Home » Potassium Channel Dysfunction in Genetic Epilepsy
Disease Discoveries

Potassium Channel Dysfunction in Genetic Epilepsy

By Will DossMar 4, 2022
Share
Facebook Twitter Email
Alfred George, Jr., MD, chair and Alfred Newton Richards Professor of Pharmacology, was lead author of the study published in JCI Insight.

Northwestern Medicine scientists have discovered functional links between dozens of potassium channel gene variants and neonatal epilepsy, according to a study published in JCI Insight.

The findings represent a significant advancement in the understanding of the gene KCNQ2, according to Alfred George, Jr., MD, chair and Alfred Newton Richards Professor of Pharmacology and lead author of the study.

KCNQ2 was among the first genes linked to genetic forms of epilepsy. Loss-of-function pathogenic variants in KCNQ2 impair voltage-gated potassium channels in neurons, creating disturbances in the electrical current that regulates neuronal excitability. Just a small proportion of the hundreds of KCNQ2 variants discovered in patients with epilepsy have been functionally evaluated, with most variants classified as “variants of uncertain significance” (VUS).

In the current study, George, along with lead author Carlos G. Vanoye, PhD, research associate professor of Pharmacology, used high-throughput patch-clamp recording to measure the effects of 81 KCNQ2 variants in Chinese hamster ovary cells. These cells naturally lack KCNQ2, allowing the scientists to introduce variants of the gene and measure changes in currents passed through potassium channels.

“Prior to our study, the entire literature had only about 50 mutations studied for their functional consequences; we studied 81,” said George, who is also director of the Center for Pharmacogenomics. “This helps demonstrate the molecular defect by which these variants  contribute to epilepsy.”

Out of the 81 KCNQ2 variants studied, nearly 60 were associated with epilepsy while the remaining were found rarely in healthy populations, according to George. Normally, each potassium channel requires two copies of genes that code for KCNQ2 proteins, and many of the variants examined were “dominant-negative,” impairing function even if paired with a normal KCNQ2 gene, poisoning the entire channel.

“Many of these variants caused a profound loss of function,” George said.

A small number of the variants had little functional difference compared to normal KCNQ2, indicating their discovery in people with epilepsy may be incidental or that dysfunction may only be present in human neurons. For all studied variants, George and his collaborators plan to share findings with genetic testing companies and update entries on ClinVar, a public archive of genetic variants administered by the National Institutes of Health.

Further, preclinical tests suggested patients with some variants may respond to treatment with the FDA-approved drug ezogabine, also known as retigabine. Administering the drug to cells with pathogenic variants restored potassium channel function in some, but the effect was highly variable among variants. Ezogabine/retigabine was pulled from the market due to low uptake and side effects, but George said he believes it could be a useful tool for patients with certain KCNQ2 variants.

“There are infants and young children with pathogenic variants who might benefit,” George said. “We want to partner with pharmaceutical companies to determine if the response of variants to retigabine that we found in the laboratory corresponds to clinical responses observed in patients — that could help move precision epilepsy treatment forward.”

This study was supported by National Institutes of Health grant NS108874.

Genetics Pharmacology Research
Share. Facebook Twitter Email

Related Posts

How ChatGPT Has, and Will Continue to, Transform Scientific Research

Mar 21, 2023

New Directions for HIV Treatment

Mar 21, 2023

Humans are Not Just Big Mice: Identifying Science’s Muscle-Scaling Problem

Mar 20, 2023

Comments are closed.

Latest News

How ChatGPT Has, and Will Continue to, Transform Scientific Research

Mar 21, 2023

New Directions for HIV Treatment

Mar 21, 2023

Humans are Not Just Big Mice: Identifying Science’s Muscle-Scaling Problem

Mar 20, 2023

AOA Honors New Members

Mar 20, 2023

Celebrating Feinberg’s 2023 Match Day

Mar 17, 2023
  • News Center Home
  • Categories
  • Press Release
  • Media Coverage
  • Editor’s Picks
  • News Archives
  • About Us
Flickr Photos
_5NM1245
230204_SERIO_MANDELL_Feinberg_Formal_0928
_5NM1715
_5NM0526
_5NM1026 (1)
_5NM1906
_5NM2173
230204_SERIO_MANDELL_Feinberg_Formal_0896
230204_SERIO_MANDELL_Feinberg_Formal_1113
230204_SERIO_MANDELL_Feinberg_Formal_1868
230204_SERIO_MANDELL_Feinberg_Formal_1237
230204_SERIO_MANDELL_Feinberg_Formal_1172

Northwestern University logo

Northwestern University Feinberg School of Medicine

RSS Facebook Twitter LinkedIn Flickr YouTube Instagram
Copyright © 2023 Northwestern University
  • Contact Northwestern University
  • Disclaimer
  • Campus Emergency Information
  • Policy Statements

Type above and press Enter to search. Press Esc to cancel.