Journal article
Drosophila carrying epilepsy-associated variants in the vitamin B6 metabolism gene PNPO display allele- and diet-dependent phenotypes
Proceedings of the National Academy of Sciences - PNAS, Vol.119(9), e2115524119
03/01/2022
DOI: 10.1073/pnas.2115524119
PMCID: PMC8892510
PMID: 35217610
Abstract
Pyridox(am)ine 5
-phosphate oxidase (PNPO) catalyzes the rate-limiting step in the synthesis of pyridoxal 5
-phosphate (PLP), the active form of vitamin B6 required for the synthesis of neurotransmitters gamma-aminobutyric acid (GABA) and the monoamines. Pathogenic variants in
have been increasingly identified in patients with neonatal epileptic encephalopathy and early-onset epilepsy. These patients often exhibit different types of seizures and variable comorbidities. Recently, the
gene has also been implicated in epilepsy in adults. It is unclear how these phenotypic variations are linked to specific
alleles and to what degree diet can modify their expression. Using CRISPR-Cas9, we generated four knock-in
alleles,
,
,
, and
, in which the endogenous
was replaced by wild-type human
complementary DNA (cDNA) and three epilepsy-associated variants. We found that these knock-in flies exhibited a wide range of phenotypes, including developmental impairments, abnormal locomotor activities, spontaneous seizures, and shortened life span. These phenotypes are allele dependent, varying with the known biochemical severity of these mutations and our characterized molecular defects. We also showed that diet treatments further diversified the phenotypes among alleles, and PLP supplementation at larval and adult stages prevented developmental impairments and seizures in adult flies, respectively. Furthermore, we found that h
had a significant dominant-negative effect, rendering heterozygous flies susceptible to seizures and premature death. Together, these results provide biological bases for the various phenotypes resulting from multifunction of
, specific molecular and/or genetic properties of each
variant, and differential allele-diet interactions.
Details
- Title: Subtitle
- Drosophila carrying epilepsy-associated variants in the vitamin B6 metabolism gene PNPO display allele- and diet-dependent phenotypes
- Creators
- Wanhao Chi - Department of Neurobiology, University of Chicago, Chicago, IL 60637Atulya S R Iyengar - Iowa Neuroscience Institute, University of Iowa, Iowa City, IA 52242Wenqin Fu - Department of Neurobiology, University of Chicago, Chicago, IL 60637Wei Liu - Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, ChinaAbigayle E Berg - Department of Biology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA 52242Chun-Fang Wu - Iowa Neuroscience Institute, University of Iowa, Iowa City, IA 52242Xiaoxi Zhuang - Grossman Institute for Neuroscience, Quantitative Biology and Human Behavior, University of Chicago, Chicago, IL 60637
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.119(9), e2115524119
- DOI
- 10.1073/pnas.2115524119
- PMID
- 35217610
- PMCID
- PMC8892510
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Grant note
- DOI: 10.13039/100006955, name: Office of Extramural Research, National Institutes of Health, award: T32MH020065; DOI: 10.13039/100006955, name: Office of Extramural Research, National Institutes of Health, award: T32DA434693; DOI: 10.13039/100006955, name: Office of Extramural Research, National Institutes of Health, award: R01NS111122
- Language
- English
- Date published
- 03/01/2022
- Academic Unit
- Iowa Neuroscience Institute; Biology
- Record Identifier
- 9984222806002771
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