{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T14:01:44Z","timestamp":1792677704671,"version":"4.5.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2015,3,1]],"date-time":"2015-03-01T00:00:00Z","timestamp":1425168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,3,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>In humans, loss of function mutations in the SAMHD1 (AGS5) gene cause a severe form of Aicardi-Gouti\u00e8res 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.<\/jats:p>","DOI":"10.4049\/jimmunol.1403157","type":"journal-article","created":{"date-parts":[[2015,2,12]],"date-time":"2015-02-12T06:11:17Z","timestamp":1423721477000},"page":"2819-2825","source":"Crossref","is-referenced-by-count":45,"title":["Characterization of <i>samhd1<\/i> Morphant Zebrafish Recapitulates Features of the Human Type I Interferonopathy Aicardi-Gouti\u00e8res Syndrome"],"prefix":"10.1093","volume":"194","author":[{"given":"Paul R","family":"Kasher","sequence":"first","affiliation":[{"name":"Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester , Manchester M13 9WL ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma M","family":"Jenkinson","sequence":"additional","affiliation":[{"name":"Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester , Manchester M13 9WL ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Briolat","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Macrophages et D\u00e9veloppement de l\u2019Immunit\u00e9 , F-75015 Paris ,","place":["France"]},{"name":"Centre National de la Recherche Scientifique, Unit\u00e9 de Recherche Associ\u00e9e 2578 , F-75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Gent","sequence":"additional","affiliation":[{"name":"Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester , Manchester M13 9WL ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Morrissey","sequence":"additional","affiliation":[{"name":"Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester , Manchester M13 9WL ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo A H","family":"Zeef","sequence":"additional","affiliation":[{"name":"Faculty of Life Sciences, University of Manchester , Manchester M13 9PT ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gillian I","family":"Rice","sequence":"additional","affiliation":[{"name":"Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester , Manchester M13 9WL ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"Levraud","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Macrophages et D\u00e9veloppement de l\u2019Immunit\u00e9 , F-75015 Paris ,","place":["France"]},{"name":"Centre National de la Recherche Scientifique, Unit\u00e9 de Recherche Associ\u00e9e 2578 , F-75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanick J","family":"Crow","sequence":"additional","affiliation":[{"name":"Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester , Manchester M13 9WL ,","place":["United Kingdom"]},{"name":"Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, Necker Hospital for Sick Children , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,3,15]]},"reference":[{"key":"2025030705312604500_r1","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/0022-510X(88)90125-6","article-title":"Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy","volume":"84","author":"Lebon","year":"1988","journal-title":"J. Neurol. Sci."},{"key":"2025030705312604500_r2","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1016\/S1474-4422(13)70258-8","article-title":"Assessment of interferon-related biomarkers in Aicardi-Gouti\u00e8res syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study","volume":"12","author":"Rice","year":"2013","journal-title":"Lancet Neurol."},{"key":"2025030705312604500_r3","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/ng1845","article-title":"Mutations in the gene encoding the 3\u2032-5\u2032 DNA exonuclease TREX1 cause Aicardi-Gouti\u00e8res syndrome at the AGS1 locus","volume":"38","author":"Crow","year":"2006","journal-title":"Nat. Genet."},{"key":"2025030705312604500_r4","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1038\/ng1842","article-title":"Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Gouti\u00e8res syndrome and mimic congenital viral brain infection","volume":"38","author":"Crow","year":"2006","journal-title":"Nat. Genet."},{"key":"2025030705312604500_r5","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1038\/ng.373","article-title":"Mutations involved in Aicardi-Gouti\u00e8res syndrome implicate SAMHD1 as regulator of the innate immune response","volume":"41","author":"Rice","year":"2009","journal-title":"Nat. Genet."},{"key":"2025030705312604500_r6","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/ng.2933","article-title":"Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling","volume":"46","author":"Rice","year":"2014","journal-title":"Nat. Genet."},{"key":"2025030705312604500_r7","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1038\/ng.2414","article-title":"Mutations in ADAR1 cause Aicardi-Gouti\u00e8res syndrome associated with a type I interferon signature","volume":"44","author":"Rice","year":"2012","journal-title":"Nat. Genet."},{"key":"2025030705312604500_r8","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/nature10623","article-title":"HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase","volume":"480","author":"Goldstone","year":"2011","journal-title":"Nature"},{"key":"2025030705312604500_r9","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/ni.2236","article-title":"SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates","volume":"13","author":"Lahouassa","year":"2012","journal-title":"Nat. Immunol."},{"key":"2025030705312604500_r10","doi-asserted-by":"crossref","first-page":"E232","DOI":"10.1073\/pnas.1104699108","article-title":"Cerebral vasculopathy is a common feature in Aicardi-Goutieres syndrome associated with SAMHD1 mutations","volume":"108","author":"du Moulin","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030705312604500_r11","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1111\/j.1469-8749.2010.03727.x","article-title":"Intracerebral large artery disease in Aicardi-Gouti\u00e8res syndrome implicates SAMHD1 in vascular homeostasis","volume":"52","author":"Ramesh","year":"2010","journal-title":"Dev. Med. Child Neurol."},{"key":"2025030705312604500_r12","doi-asserted-by":"crossref","first-page":"E1836","DOI":"10.1002\/humu.21357","article-title":"Cerebral arterial stenoses and stroke: novel features of Aicardi-Gouti\u00e8res syndrome caused by the Arg164X mutation in SAMHD1 are associated with altered cytokine expression","volume":"31","author":"Thiele","year":"2010","journal-title":"Hum. Mutat."},{"key":"2025030705312604500_r13","doi-asserted-by":"crossref","first-page":"5372","DOI":"10.1073\/pnas.1014265108","article-title":"Homozygous mutation in SAMHD1 gene causes cerebral vasculopathy and early onset stroke","volume":"108","author":"Xin","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030705312604500_r14","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.celrep.2013.07.037","article-title":"Mouse SAMHD1 has antiretroviral activity and suppresses a spontaneous cell-intrinsic antiviral response","volume":"4","author":"Behrendt","year":"2013","journal-title":"Cell Reports"},{"key":"2025030705312604500_r15","doi-asserted-by":"crossref","first-page":"2454","DOI":"10.1038\/emboj.2013.163","article-title":"SAMHD1-dependent retroviral control and escape in mice","volume":"32","author":"Rehwinkel","year":"2013","journal-title":"EMBO J."},{"key":"2025030705312604500_r16","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1242\/dmm.007138","article-title":"A model 450 million years in the making: zebrafish and vertebrate immunity","volume":"5","author":"Renshaw","year":"2012","journal-title":"Dis. Model. Mech."},{"key":"2025030705312604500_r17","doi-asserted-by":"crossref","first-page":"159807","DOI":"10.1155\/2012\/159807","article-title":"Pathogen recognition and activation of the innate immune response in zebrafish","volume":"2012","author":"van der Vaart","year":"2012","journal-title":"Adv. Hematol."},{"key":"2025030705312604500_r18","doi-asserted-by":"crossref","first-page":"4328","DOI":"10.4049\/jimmunol.1302611","article-title":"Contrasted innate responses to two viruses in zebrafish: insights into the ancestral repertoire of vertebrate IFN-stimulated genes","volume":"192","author":"Briolat","year":"2014","journal-title":"J. Immunol."},{"key":"2025030705312604500_r19","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1006\/dbio.2002.0711","article-title":"In vivo imaging of embryonic vascular development using transgenic zebrafish","volume":"248","author":"Lawson","year":"2002","journal-title":"Dev. Biol."},{"key":"2025030705312604500_r20","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1038\/ni1007","article-title":"Transplantation and in vivo imaging of multilineage engraftment in zebrafish bloodless mutants","volume":"4","author":"Traver","year":"2003","journal-title":"Nat. Immunol."},{"key":"2025030705312604500_r21","doi-asserted-by":"crossref","first-page":"e1003619","DOI":"10.1371\/journal.ppat.1003619","article-title":"Real-time whole-body visualization of Chikungunya Virus infection and host interferon response in zebrafish","volume":"9","author":"Palha","year":"2013","journal-title":"PLoS Pathog."},{"key":"2025030705312604500_r22","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/aja.1002030302","article-title":"Stages of embryonic development of the zebrafish","volume":"203","author":"Kimmel","year":"1995","journal-title":"Dev. Dyn."},{"key":"2025030705312604500_r23","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1056\/NEJMoa1307361","article-title":"Early-onset stroke and vasculopathy associated with mutations in ADA2","volume":"370","author":"Zhou","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"2025030705312604500_r24","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1093\/hmg\/ddr034","article-title":"Impairment of the tRNA-splicing endonuclease subunit 54 (tsen54) gene causes neurological abnormalities and larval death in zebrafish models of pontocerebellar hypoplasia","volume":"20","author":"Kasher","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"2025030705312604500_r25","doi-asserted-by":"crossref","first-page":"3103","DOI":"10.1242\/dev.112003","article-title":"Out with the old, in with the new: reassessing morpholino knockdowns in light of genome editing technology","volume":"141","author":"Schulte-Merker","year":"2014","journal-title":"Development"},{"key":"2025030705312604500_r26","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nature09907","article-title":"A diverse range of gene products are effectors of the type I interferon antiviral response","volume":"472","author":"Schoggins","year":"2011","journal-title":"Nature"},{"key":"2025030705312604500_r27","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/ni.1680","article-title":"ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling","volume":"10","author":"Hartner","year":"2009","journal-title":"Nat. Immunol."},{"key":"2025030705312604500_r28","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1016\/j.celrep.2014.10.041","article-title":"The RNA-editing enzyme ADAR1 controls innate immune responses to RNA","volume":"9","author":"Mannion","year":"2014","journal-title":"Cell Reports"},{"key":"2025030705312604500_r29","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S0378-1119(00)00175-X","article-title":"Comparative analysis of the DRADA A-to-I RNA editing gene from mammals, pufferfish and zebrafish","volume":"250","author":"Slavov","year":"2000","journal-title":"Gene"},{"key":"2025030705312604500_r30","doi-asserted-by":"crossref","first-page":"4904","DOI":"10.1016\/j.jmb.2013.09.033","article-title":"The antiviral innate immune response in fish: evolution and conservation of the IFN system","volume":"425","author":"Langevin","year":"2013","journal-title":"J. Mol. Biol."},{"key":"2025030705312604500_r31","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.immuni.2011.11.018","article-title":"Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease","volume":"36","author":"Gall","year":"2012","journal-title":"Immunity"},{"key":"2025030705312604500_r32","doi-asserted-by":"crossref","first-page":"6719","DOI":"10.1128\/MCB.24.15.6719-6727.2004","article-title":"Gene-targeted mice lacking the Trex1 (DNase III) 3\u2032\u2014 &gt;5\u2032 DNA exonuclease develop inflammatory myocarditis","volume":"24","author":"Morita","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"2025030705312604500_r33","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.cell.2008.06.032","article-title":"Trex1 prevents cell-intrinsic initiation of autoimmunity","volume":"134","author":"Stetson","year":"2008","journal-title":"Cell"},{"key":"2025030705312604500_r34","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.immuni.2013.12.014","article-title":"Autoimmune disorders associated with gain of function of the intracellular sensor MDA5","volume":"40","author":"Funabiki","year":"2014","journal-title":"Immunity"},{"key":"2025030705312604500_r35","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1084\/jem.20120876","article-title":"Mammalian RNase H2 removes ribonucleotides from DNA to maintain genome integrity","volume":"209","author":"Hiller","year":"2012","journal-title":"J. Exp. Med."},{"key":"2025030705312604500_r36","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1016\/j.cell.2012.04.011","article-title":"Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development","volume":"149","author":"Reijns","year":"2012","journal-title":"Cell"},{"key":"2025030705312604500_r37","doi-asserted-by":"crossref","first-page":"13996","DOI":"10.1073\/pnas.0700947104","article-title":"pak2a mutations cause cerebral hemorrhage in redhead zebrafish","volume":"104","author":"Buchner","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030705312604500_r38","doi-asserted-by":"crossref","first-page":"13990","DOI":"10.1073\/pnas.0700825104","article-title":"A betaPix Pak2a signaling pathway regulates cerebral vascular stability in zebrafish","volume":"104","author":"Liu","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030705312604500_r39","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.fsi.2009.11.012","article-title":"Cloning of common carp SOCS-3 gene and its expression during embryogenesis, GH-transgene and viral infection","volume":"28","author":"Xiao","year":"2010","journal-title":"Fish Shellfish Immunol."},{"key":"2025030705312604500_r40","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nature13801","article-title":"Human intracellular ISG15 prevents interferon-\u03b1\/\u03b2 over-amplification and auto-inflammation","volume":"517","author":"Zhang","year":"2015","journal-title":"Nature"},{"key":"2025030705312604500_r41","doi-asserted-by":"crossref","first-page":"10025","DOI":"10.1128\/JVI.01294-12","article-title":"Zebrafish ISG15 exerts a strong antiviral activity against RNA and DNA viruses and regulates the interferon response","volume":"87","author":"Langevin","year":"2013","journal-title":"J. Virol."},{"key":"2025030705312604500_r42","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1212\/WNL.0b013e3182872694","article-title":"Elevation of proinflammatory cytokines in patients with Aicardi-Gouti\u00e8res syndrome","volume":"80","author":"Takanohashi","year":"2013","journal-title":"Neurology"},{"key":"2025030705312604500_r43","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1002\/glia.20639","article-title":"Astrocytes produce interferon-alpha and CXCL10, but not IL-6 or CXCL8, in Aicardi-Gouti\u00e8res syndrome","volume":"56","author":"van Heteren","year":"2008","journal-title":"Glia"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/194\/6\/2819\/62236833\/1403157.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/194\/6\/2819\/62236833\/1403157.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T06:50:39Z","timestamp":1741330239000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/194\/6\/2819\/7961009"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,3]]},"references-count":43,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2015,3,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1403157","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,3]]},"published":{"date-parts":[[2015,3]]}}}