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
-
- Blotting, Western
- Sequence Homology, Amino Acid
- Amino Acid Sequence
- Interferons/genetics
- Interferons/metabolism
- Gene Expression Regulation, Developmental
- Interferon Type I/genetics*
- Interferon Type I/metabolism
- Autoimmune Diseases of the Nervous System/embryology
- Autoimmune Diseases of the Nervous System/genetics*
- Autoimmune Diseases of the Nervous System/metabolism
- Intracranial Hemorrhages/embryology
- Intracranial Hemorrhages/genetics
- Intracranial Hemorrhages/metabolism
- Acid Anhydride Hydrolases/genetics*
- Acid Anhydride Hydrolases/metabolism
- Microscopy, Fluorescence
- Immunity, Innate/genetics
- Cerebral Ventricles/abnormalities
- Cerebral Ventricles/metabolism
- Animals
- Gene Knockdown Techniques*
- Reverse Transcriptase Polymerase Chain Reaction
- Nervous System Malformations/embryology
- Nervous System Malformations/genetics*
- Nervous System Malformations/metabolism
- Disease Models, Animal
- Rhombencephalon/abnormalities
- Rhombencephalon/metabolism
- Zebrafish Proteins/deficiency
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- Animals, Genetically Modified
- Adenosine Deaminase/genetics
- Adenosine Deaminase/metabolism
- Molecular Sequence Data
- Humans
- 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