PUBLICATION

Chemical screens in a zebrafish model of CHARGE syndrome identifies small molecules that ameliorates disease like phenotypes in embryo

Authors
Asad, Z., Sachidanandan, C.
ID
ZDB-PUB-190507-30
Date
2019
Source
European Journal of Medical Genetics   63(2): 103661 (Journal)
Registered Authors
Sachidanandan, Chetana
Keywords
CHARGE syndrome, CHD7, CHIC-35, DAPT, Drug discovery, M344, Procainamide, Zebrafish
MeSH Terms
  • Cartilage/drug effects
  • Cartilage/pathology
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
  • DNA (Cytosine-5-)-Methyltransferase 1/antagonists & inhibitors
  • Gene Knockdown Techniques
  • CHARGE Syndrome/drug therapy*
  • CHARGE Syndrome/genetics
  • CHARGE Syndrome/physiopathology*
  • Animals
  • Embryo, Nonmammalian/diagnostic imaging
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/metabolism
  • Embryo, Nonmammalian/physiopathology
  • LIM-Homeodomain Proteins/genetics
  • LIM-Homeodomain Proteins/metabolism
  • Sirtuin 1/antagonists & inhibitors
  • Dipeptides/pharmacology*
  • Dipeptides/therapeutic use
  • DNA-Binding Proteins/genetics*
  • DNA-Binding Proteins/metabolism
  • Receptors, Notch/antagonists & inhibitors
  • Histone Deacetylase Inhibitors/pharmacology
  • Histone Deacetylase Inhibitors/therapeutic use
  • Zebrafish/embryology*
  • Zebrafish/genetics
  • Procainamide/pharmacology*
  • Procainamide/therapeutic use
  • Animals, Genetically Modified
  • Disease Models, Animal
  • Vorinostat/pharmacology*
  • Vorinostat/therapeutic use
  • Neurons/drug effects
  • Neurons/pathology
  • DNA Helicases/genetics*
  • DNA Helicases/metabolism
  • Transcription Factors/genetics
  • Transcription Factors/metabolism
  • Nerve Fibers, Myelinated/drug effects
  • Nerve Fibers, Myelinated/pathology
(all 40)
PubMed
31051269 Full text @ Eur. J. Med. Genet.
Abstract
CHARGE syndrome is an autosomal dominant congenital disorder caused primarily by mutations in the CHD7 gene. Using a small molecule screen in a zebrafish model of CHARGE syndrome, we identified 4 compounds that rescue embryos from disease-like phenotypes. Our screen yielded DAPT, a Notch signaling inhibitor that could ameliorate the craniofacial, cranial neuronal and myelination defects in chd7 morphant zebrafish embryos. We discovered that Procainamide, an inhibitor of DNA methyltransferase 1, was able to recover the pattern of expression of isl2a, a cranial neuronal marker while also reducing the effect on craniofacial cartilage and myelination. M344, an inhibitor of Histone deacetylases had a strong recovery effect on craniofacial cartilage defects and could also modestly revert the myelination defects in zebrafish embryos. CHIC-35, a SIRT1 inhibitor partially restored the expression of isl2a in cranial neurons while causing a partial reversion of myelination and craniofacial cartilage defects. Our results suggest that a modular approach to phenotypic rescue in multi-organ syndromes might be a more successful approach to treat these disorders. Our findings also open up the possibility of using these compounds for other disorders with shared phenotypes.
Genes / Markers
Figures
No images available
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Your Input Welcome
We welcome your input and comments. Please use this form to recommend updates to the information in ZFIN. We appreciate as much detail as possible and references as appropriate. We will review your comments promptly.
Citation
Asad, Z., Sachidanandan, C. (2019) Chemical screens in a zebrafish model of CHARGE syndrome identifies small molecules that ameliorates disease like phenotypes in embryo. European Journal of Medical Genetics. 63(2):103661.