PUBLICATION
Characterization of samhd1 Morphant Zebrafish Recapitulates Features of the Human Type I Interferonopathy Aicardi-Goutières Syndrome
- Authors
- Kasher, P.R., Jenkinson, E.M., Briolat, V., Gent, D., Morrissey, C., Zeef, L.A., Rice, G.I., Levraud, J.P., Crow, Y.J.
- ID
- ZDB-PUB-150213-4
- Date
- 2015
- Source
- Journal of immunology (Baltimore, Md. : 1950) 194(6): 2819-25 (Journal)
- Registered Authors
- Briolat, Valerie, Kasher, Paul, Levraud, Jean-Pierre
- Keywords
- none
- MeSH Terms
-
- Molecular Sequence Data
- Gene Expression Regulation, Developmental
- Adenosine Deaminase/genetics
- Adenosine Deaminase/metabolism
- Rhombencephalon/abnormalities
- Rhombencephalon/metabolism
- Amino Acid Sequence
- Acid Anhydride Hydrolases/genetics*
- Acid Anhydride Hydrolases/metabolism
- Interferons/genetics
- Interferons/metabolism
- Animals
- Microscopy, Fluorescence
- Sequence Homology, Amino Acid
- Nervous System Malformations/embryology
- Nervous System Malformations/genetics*
- Nervous System Malformations/metabolism
- Humans
- Interferon Type I/genetics*
- Interferon Type I/metabolism
- Disease Models, Animal
- Cerebral Ventricles/abnormalities
- Cerebral Ventricles/metabolism
- Immunity, Innate/genetics
- Reverse Transcriptase Polymerase Chain Reaction
- Blotting, Western
- Autoimmune Diseases of the Nervous System/embryology
- Autoimmune Diseases of the Nervous System/genetics*
- Autoimmune Diseases of the Nervous System/metabolism
- Gene Knockdown Techniques*
- Zebrafish Proteins/deficiency
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- Intracranial Hemorrhages/embryology
- Intracranial Hemorrhages/genetics
- Intracranial Hemorrhages/metabolism
- Animals, Genetically Modified
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 25672750 Full text @ J. Immunol.
Citation
Kasher, P.R., Jenkinson, E.M., Briolat, V., Gent, D., Morrissey, C., Zeef, L.A., Rice, G.I., Levraud, J.P., Crow, Y.J. (2015) Characterization of samhd1 Morphant Zebrafish Recapitulates Features of the Human Type I Interferonopathy Aicardi-Goutières Syndrome. Journal of immunology (Baltimore, Md. : 1950). 194(6):2819-25.
Abstract
In humans, loss of function mutations in the SAMHD1 (AGS5) gene cause a severe form of Aicardi-Goutières syndrome (AGS), an inherited inflammatory-mediated encephalopathy characterized by increased type I IFN activity and upregulation of IFN-stimulated genes (ISGs). In particular, SAMHD1-related AGS is associated with a distinctive cerebrovascular pathology that commonly leads to stroke. Although inflammatory responses are observed in immune cells cultured from Samhd1 null mouse models, these mice are physically healthy, specifically lacking a brain phenotype. We have investigated the use of zebrafish as an alternative system for generating a clinically relevant model of SAMHD1-related AGS. Using temporal gene knockdown of zebrafish samhd1, we observe hindbrain ventricular swelling and brain hemorrhage. Furthermore, loss of samhd1 or of another AGS-associated gene, adar, leads to a significant upregulation of innate immune-related genes and an increase in the number of cells expressing the zebrafish type I IFN ifnphi1. To our knowledge, this is the first example of an in vivo model of AGS that recapitulates features of both the innate immune and neurological characteristics of the disease. The phenotypes associated with loss of samhd1 and adar suggest a function of these genes in controlling innate immune processes conserved to zebrafish, thereby also contributing to our understanding of antiviral signaling in this model organism.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping