The prolonged and severe seizures suffered by those with pyridoxine-dependent epilepsy (PDE) can lead to brain dysfunction and death if not treated. Standard antiepileptic drugs are typically ineffective for people with this rare genetic disorder—instead, they need high doses of vitamin B6 in the form of pyridoxine or pyridoxal 5′-phosphate. But even with this supplementation, people with PDE often have lingering problems, and over 75% experience neurodevelopmental delays.
Although more than sixty years have passed since PDE was first described, and treatment remains inadequate for resolving all the condition’s comorbidities, little is known about the pathophysiology of PDE. This is partially because no animal model has been available to study PDE—until now. In this month’s issue of GENETICS, Pena et al. report that they have generated zebrafish with mutations in the same gene that causes PDE when mutated in humans. This gene, ALDH7A1, encodes an enzyme called antiquitin, which is important for the breakdown of the amino acid lysine.
The researchers used CRISPR/Cas9-based gene editing to alter the fish version of the gene, rendering it nonfunctional. They found that fish carrying two damaged copies of the gene develop recurrent seizures at an early age, just like humans with PDE do. Without intervention with vitamin B6, the fish’s seizures result in death. The fish also have the same biochemical abnormalities as humans with PDE do, including a buildup of toxic lysine byproducts. The researchers also found several other previously unknown biochemical abnormalities in the fish’s brains, which may help understand the disorder.
The fact that these fish recapitulate human PDE so well—at both the biochemical and organismal levels—will make them a valuable model for further studying the condition. Not only are zebrafish commonly used model organisms with a multitude of tools available for manipulating their genetics, they’re also often used in epilepsy research with many established protocols for studying the topic, making them an ideal choice for investigating this challenging disorder.
CITATION:
Pena, I.; Roussel, Y.; Daniel, K.; Mongeon, K.; Johnstone, D.; Weinschutz Mendes, H.; Bosma, M.; Saxena, V.; Lepage, N.; Chakraborty, P.; Dyment, D.; van Karnebeek, C.; Verhoeven-Duif, N.; Vu Bui, T.; Boycott, K.; Ekker, M.; MacKenzie, A. Pyridoxine-Dependent Epilepsy in Zebrafish Caused by Aldh7a1 Deficiency.
GENETICS, 207(4), 1501-1518.
DOI: 10.1534/genetics.117.300137
http://www.genetics.org/content/207/4/1501
Nicole Haloupek is a freelance science writer and a recent graduate of UC Berkeley's molecular and cell biology PhD program.
View all posts by Nicole Haloupek »Read more in
-
Hongyu Zhao joins GENETICS as new Senior Editor
A new senior editor is joining GENETICS in the Statistical Genetics and Genomics section. We’re excited to welcome Hongyu Zhao to the editorial team. Hongyu ZhaoSenior Editor Hongyu Zhao is the Ira V. Hiscock Professor of Biostatistics, Professor of Genetics, and Professor of Statistics and Data Science at Yale University. He received his BS in…
-
GSA Member Julio Molina Pineda Receives DeLill Nasser Award, Shines at TAGC 2024
“At any career stage, the GSA membership is an amazing investment for any genetics professional!” Julio Molina Pineda is a PhD Candidate in Cell and Molecular Biology and a Research Assistant at the University of Arkansas, and a Doctoral Academy Fellow at the Lewis Lab. In 2023, Julio was awarded the DeLill Nasser Award for…
-
In Memoriam: Ellsworth Herman Grell (1932–2023), a pioneer of Drosophila genome engineering and annotation
Ellsworth (Ed) Grell blessed the Drosophila community through three enduring legacies: as a pioneer of chromosome mechanics, as a primary organizer and synthesizer of genetic knowledge in Drosophila, and as a graceful mentor to those fortunate to have known him personally. Ed grew up in rural Nebraska, completed his undergraduate studies at Iowa State, and…
-
Congratulations to the #Fungal24 Poster Award winners!
We are pleased to announce the recipients of the GSA Poster Awards for posters presented at the 32nd Fungal Genetics Conference! Undergraduate and graduate student members of GSA were eligible for the awards, and a hard-working team of judges made the determinations. Congratulations to all! Felicia Ebot Ojong, The University of Georgia My research is focused…
-
Poster presentation tips for TAGC 2024
You’ve been selected to present a poster at The Allied Genetics Conference 2024 in March—you’ve celebrated, made plans to attend, now what? This is an exciting opportunity to showcase your research and engage with fellow members of the genetics community, so you want to make sure you’re prepared. We wanted to offer you some tips…
-
Maximize your TAGC 2024 experience
A guide to all that National Harbor & DC have to offer Are you joining us for The Allied Genetics Conference 2024 in March? Make the most of your #TAGC24 experience in National Harbor! We know the science will keep you busy, but you deserve to unwind and have some fun, so we’ve curated a…
-
Early Career Leadership Spotlight: Sarah Petrosky
We’re taking time to get to know the members of the GSA’s Early Career Scientist Committees. Join us to learn more about our early career scientist advocates. Sarah PetroskyMultimedia SubcommitteeUniversity of Pittsburgh Research Interest I am interested in understanding adaptation that has been happening recently in populations by dissecting the ways that genes underlying an adaptation…
-
TAGC 2024 Early Career Award Winners
GSA is pleased to announce the winners of the early career awards presented at The Allied Genetics Conference 2024. These awards are specific to particular TAGC communities and recognize early career scientists’ outstanding work on their respective research organisms. The awardees will present their talks in keynote sessions at TAGC 2024. Don’t miss the opportunity…
-
Preeminent geneticists recognized with revamped GSA Awards
In 2022, GSA’s Board of Directors launched an audit to review the five major awards conferred by the Society. Today, we are thrilled to announce the recipients of the reimagined GSA Awards, including the new Genetics Society of America Early Career Medal. The scientists honored this year are recognized by their peers for their outstanding…
-
Fly Board funds outreach programs to spread the word about Drosophila research
In 2020, the Fly Board voted to use part of its reserve fund to support efforts to increase trainee participation as well as equity and diversity in the Drosophila community. An awards committee decides how the money will be spent each year, and from 2020–2022, the committee posted a very broad call for applications from…
-
New members of the GSA Board of Directors: 2024–2026
We are pleased to announce the election of four new leaders to the GSA Board of Directors: 2024 Vice President/2025 President Brenda Andrews Professor, University of Toronto It’s an honor to continue my association with the Society by serving as Vice President of the Board of Directors. I have broad knowledge of the ongoing activities…