Characterization of samhd1 Morphant Zebrafish Recapitulates Features of the Human Type I Interferonopathy Aicardi-Goutières Syndrome

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.

SAMHD1‐deficient fibroblasts from Aicardi‐Goutières Syndrome patients can escape senescence and accumulate mutations

“…[18][19][20] In the four AGS lines studied here, we observed two different patterns of growth in vitro, namely normal proliferation or precocious senescence (Figure 2), connected to different gene expression patterns. This block of the cell cycle conflicts with the basically normal development of human patients and animal models of SAMHD1 deficiency.…”

“…Loss of SAMHD1 is accompanied by expansion of the dNTP pools, particularly large in non-dividing cells. [18][19][20] Pool imbalances have documented destabilizing effects, inducing misincorporation of the dNTP present in excess, interfering with correct chain elongation and causing structural alterations of chromosomes. Purine dNTPs increased more than pyrimidine dNTPs in transformed cells, 12,13 in primary fibroblasts, 8 and in whole mouse embryos.…”

SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity

“…A more promising animal system for modeling SAMHD1 induced AGS might be found in zebra fish. In this alternative to mouse models, zebra fish exhibit similar interferon overexpression and cerebrovascular pathologies upon deletion of SAMHD1 to those clinically observed in AGS patients (192). …”

Roles of SAMHD1 in antiviral defense, autoimmunity and cancer

“…96,97 While SAMHD1-deficient mice are not ideal animal models to study the mechanism of human AGS that is caused by SAMHD1 deficiency, a zebrafish model of SAMHD1 deficiency showed hindbrain ventricular swelling and brain hemorrhage. 98 Moreover, in this zebrafish model, SAMHD1 deficiency was associated with the upregulation of genes involved in innate immune responses and an enhanced expression of zebrafish type 1 IFN ifnphi1. These symptoms recapitulate features of human AGS and suggest that the SAMHD1deficient zebrafish model could be used to study how SAMHD1 dysfunction leads to abnormal IFN signaling in AGS.…”

“…Surprisingly, SAMHD1‐deficient mice are healthy and do not develop autoimmune disease although an aberrant IFN signature can be detected in some tissues and cells . While SAMHD1‐deficient mice are not ideal animal models to study the mechanism of human AGS that is caused by SAMHD1 deficiency, a zebrafish model of SAMHD1 deficiency showed hindbrain ventricular swelling and brain hemorrhage . Moreover, in this zebrafish model, SAMHD1 deficiency was associated with the upregulation of genes involved in innate immune responses and an enhanced expression of zebrafish type 1 IFN ifnphi1 .…”