PMID- 31261385
OWN - NLM
STAT- MEDLINE
DCOM- 20200309
LR  - 20220322
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 28
IP  - 18
DP  - 2019 Sep 15
TI  - Pyridox (am) ine 5'-phosphate oxidase deficiency induces seizures in Drosophila 
      melanogaster.
PG  - 3126-3136
LID - 10.1093/hmg/ddz143 [doi]
AB  - Pyridox (am) ine 5'-phosphate oxidase (PNPO) is a rate-limiting enzyme in 
      converting dietary vitamin B6 (VB6) to pyridoxal 5'-phosphate (PLP), the 
      biologically active form of VB6 and involved in the synthesis of 
      neurotransmitters including gamma-aminobutyric acid (GABA), dopamine, and serotonin. 
      In humans, PNPO mutations have been increasingly identified in neonatal epileptic 
      encephalopathy and more recently also in early-onset epilepsy. Till now, little 
      is known about the neurobiological mechanisms underlying PNPO-deficiency-induced 
      seizures due to the lack of animal models. Previously, we identified a c.95 C>A 
      missense mutation in sugarlethal (sgll)-the Drosophila homolog of human PNPO 
      (hPNPO)-and found mutant (sgll95) flies exhibiting a lethal phenotype on a diet 
      devoid of VB6. Here, we report the establishment of both sgll95 and ubiquitous 
      sgll knockdown (KD) flies as valid animal models of PNPO-deficiency-induced 
      epilepsy. Both sgll95 and sgll KD flies exhibit spontaneous seizures before they 
      die. Electrophysiological recordings reveal that seizures caused by PNPO 
      deficiency have characteristics similar to that in flies treated with the GABA 
      antagonist picrotoxin. Both seizures and lethality are associated with low PLP 
      levels and can be rescued by ubiquitous expression of wild-type sgll or hPNPO, 
      suggesting the functional conservation of the PNPO enzyme between humans and 
      flies. Results from cell type-specific sgll KD further demonstrate that PNPO in 
      the brain is necessary for seizure prevention and survival. Our establishment of 
      the first animal model of PNPO deficiency will lead to better understanding of 
      VB6 biology, the PNPO gene and its mutations discovered in patients, and can be a 
      cost-effective system to test therapeutic strategies.
CI  - (c) The Author(s) 2019. Published by Oxford University Press. All rights reserved. 
      For Permissions, please email: journals.permissions@oup.com.
FAU - Chi, Wanhao
AU  - Chi W
AD  - Committee on Genetics, Genomics and Systems Biology.
AD  - Department of Neurobiology, University of Chicago, Chicago, IL, USA.
FAU - Iyengar, Atulya S R
AU  - Iyengar ASR
AD  - Department of Biology, College of Liberal Arts and Sciences, University of Iowa, 
      Iowa City, IA, USA.
FAU - Albersen, Monique
AU  - Albersen M
AD  - Section Metabolic Diagnostics, Department of Medical Genetics, University Medical 
      Center Utrecht, Utrecht, EA, The Netherlands.
FAU - Bosma, Marjolein
AU  - Bosma M
AD  - Section Metabolic Diagnostics, Department of Medical Genetics, University Medical 
      Center Utrecht, Utrecht, EA, The Netherlands.
FAU - Verhoeven-Duif, Nanda M
AU  - Verhoeven-Duif NM
AD  - Section Metabolic Diagnostics, Department of Medical Genetics, University Medical 
      Center Utrecht, Utrecht, EA, The Netherlands.
FAU - Wu, Chun-Fang
AU  - Wu CF
AD  - Department of Biology, College of Liberal Arts and Sciences, University of Iowa, 
      Iowa City, IA, USA.
FAU - Zhuang, Xiaoxi
AU  - Zhuang X
AD  - Department of Neurobiology, University of Chicago, Chicago, IL, USA.
LA  - eng
GR  - R01 AG051513/AG/NIA NIH HHS/United States
GR  - R01 GM100768/GM/NIGMS NIH HHS/United States
GR  - T32 DA043469/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - EC 1.4.3.5 (Pyridoxaminephosphate Oxidase)
RN  - Pyridoxamine 5-Prime-Phosphate Oxidase Deficiency
SB  - IM
EIN - Hum Mol Genet. 2022 Aug 17;31(15):2668. PMID: 35311996
MH  - Animal Feed
MH  - Animals
MH  - Behavior, Animal
MH  - Brain/metabolism/physiopathology
MH  - Brain Diseases, Metabolic/*diagnosis/*genetics/metabolism
MH  - Disease Models, Animal
MH  - Drosophila melanogaster
MH  - Epilepsy
MH  - Gene Knockdown Techniques
MH  - Genes, Lethal
MH  - Genetic Association Studies
MH  - Genetic Predisposition to Disease
MH  - Humans
MH  - Hypoxia-Ischemia, Brain/*diagnosis/*genetics/metabolism
MH  - Metabolic Networks and Pathways
MH  - *Mutation
MH  - *Phenotype
MH  - Pyridoxaminephosphate Oxidase/*deficiency/genetics/metabolism
MH  - RNA Interference
MH  - Seizures/*diagnosis/*genetics/metabolism
PMC - PMC6737294
EDAT- 2019/07/02 06:00
MHDA- 2020/03/10 06:00
PMCR- 2020/07/02
CRDT- 2019/07/02 06:00
PHST- 2019/03/11 00:00 [received]
PHST- 2019/05/31 00:00 [revised]
PHST- 2019/06/04 00:00 [accepted]
PHST- 2019/07/02 06:00 [pubmed]
PHST- 2020/03/10 06:00 [medline]
PHST- 2019/07/02 06:00 [entrez]
PHST- 2020/07/02 00:00 [pmc-release]
AID - 5526798 [pii]
AID - ddz143 [pii]
AID - 10.1093/hmg/ddz143 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2019 Sep 15;28(18):3126-3136. doi: 10.1093/hmg/ddz143.