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Type I Interferonopathy due to a Homozygous Loss-of-Inhibitory Function Mutation in STAT2
Purpose STAT2 is both an effector and negative regulator of type I interferon (IFN-I) signalling. We describe the characterization of a novel homozygous missense STAT2 substitution in a patient with a type I interferonopathy. Methods Whole-genome sequencing (WGS) was used to identify the genetic bas...
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| Published in: | Journal of clinical immunology 2023-05, Vol.43 (4), p.808-818 |
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| container_end_page | 818 |
| container_issue | 4 |
| container_start_page | 808 |
| container_title | Journal of clinical immunology |
| container_volume | 43 |
| creator | Zhu, Gaofeng Badonyi, Mihaly Franklin, Lina Seabra, Luis Rice, Gillian I. Anne-Boland-Auge Deleuze, Jean-François El-Chehadeh, Salima Anheim, Mathieu de Saint-Martin, Anne Pellegrini, Sandra Marsh, Joseph A. Crow, Yanick J. El-Daher, Marie-Therese |
| description | Purpose
STAT2 is both an effector and negative regulator of type I interferon (IFN-I) signalling. We describe the characterization of a novel homozygous missense STAT2 substitution in a patient with a type I interferonopathy.
Methods
Whole-genome sequencing (WGS) was used to identify the genetic basis of disease in a patient with features of enhanced IFN-I signalling. After stable lentiviral reconstitution of STAT2-null human fibrosarcoma U6A cells with STAT2 wild type or p.(A219V), we performed quantitative polymerase chain reaction, western blotting, immunofluorescence, and co-immunoprecipitation to functionally characterize the p.(A219V) variant.
Results
WGS identified a rare homozygous single nucleotide transition in
STAT2
(c.656C > T), resulting in a p.(A219V) substitution, in a patient displaying developmental delay, intracranial calcification, and up-regulation of interferon-stimulated gene (ISG) expression in blood. In vitro studies revealed that the STAT2 p.(A219V) variant retained the ability to transduce an IFN-I stimulus. Notably, STAT2 p.(A219V) failed to support receptor desensitization, resulting in sustained STAT2 phosphorylation and ISG up-regulation. Mechanistically, STAT2 p.(A219V) showed defective binding to ubiquitin specific protease 18 (USP18), providing a possible explanation for the chronic IFN-I pathway activation seen in the patient.
Conclusion
Our data indicate an impaired negative regulatory role of STAT2 p.(A219V) in IFN-I signalling and that mutations in STAT2 resulting in a type I interferonopathy state are not limited to the previously reported R148 residue. Indeed, structural modelling highlights at least 3 further residues critical to mediating a STAT2-USP18 interaction, in which mutations might be expected to result in defective negative feedback regulation of IFN-I signalling. |
| doi_str_mv | 10.1007/s10875-023-01445-3 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10110676</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2802187277</sourcerecordid><originalsourceid>FETCH-LOGICAL-c509t-f2204bda9915a59efe4891e72324f270636757a13dbe6a586b258984e95564dd3</originalsourceid><addsrcrecordid>eNp9kUtvEzEUhS0EoqHwB1ggS2xgYbh-j1coqiiJFMSCsGBleWY8yVSJHeyZSsOvx-2UAl2wsqX7nXMfB6GXFN5RAP0-U6i0JMA4ASqEJPwRWlCpOWHSsMdoAUxTYqhgZ-hZzlcAwBWTT9EZV1pyoGqBvm-nk8drvA6DT51PMcSTG_YTbkePh4gdXsVj_Dnt4pjxJuZMYkfWYd_X_RDThC_H0Ax9DPjzOLjbTx_w1-1yy56jJ507ZP_i7j1H3y4_bi9WZPPl0_piuSGNBDOQjjEQdeuModJJ4zsvKkO9ZpyJjmlQN7NqR3lbe-VkpWomK1MJb6RUom35Ofow-57G-ujbxochuYM9pf7o0mSj6-2_ldDv7S5eWwqUgtKqOLydHfYPdKvlxjbeWRCcC0bVNS3sm7tuKf4YfR7ssc-NPxxc8OVElmkthDEcZEFfP0Cv4phCuYVlFTBa6QIXis1Uk8p1k-_uJ6Bgb2K2c8y2xGxvY7a8iF79vfO95HeuBeAzkEsp7Hz60_s_tr8A0GOw7w</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2802187277</pqid></control><display><type>article</type><title>Type I Interferonopathy due to a Homozygous Loss-of-Inhibitory Function Mutation in STAT2</title><source>Springer Link</source><creator>Zhu, Gaofeng ; Badonyi, Mihaly ; Franklin, Lina ; Seabra, Luis ; Rice, Gillian I. ; Anne-Boland-Auge ; Deleuze, Jean-François ; El-Chehadeh, Salima ; Anheim, Mathieu ; de Saint-Martin, Anne ; Pellegrini, Sandra ; Marsh, Joseph A. ; Crow, Yanick J. ; El-Daher, Marie-Therese</creator><creatorcontrib>Zhu, Gaofeng ; Badonyi, Mihaly ; Franklin, Lina ; Seabra, Luis ; Rice, Gillian I. ; Anne-Boland-Auge ; Deleuze, Jean-François ; El-Chehadeh, Salima ; Anheim, Mathieu ; de Saint-Martin, Anne ; Pellegrini, Sandra ; Marsh, Joseph A. ; Crow, Yanick J. ; El-Daher, Marie-Therese</creatorcontrib><description>Purpose
STAT2 is both an effector and negative regulator of type I interferon (IFN-I) signalling. We describe the characterization of a novel homozygous missense STAT2 substitution in a patient with a type I interferonopathy.
Methods
Whole-genome sequencing (WGS) was used to identify the genetic basis of disease in a patient with features of enhanced IFN-I signalling. After stable lentiviral reconstitution of STAT2-null human fibrosarcoma U6A cells with STAT2 wild type or p.(A219V), we performed quantitative polymerase chain reaction, western blotting, immunofluorescence, and co-immunoprecipitation to functionally characterize the p.(A219V) variant.
Results
WGS identified a rare homozygous single nucleotide transition in
STAT2
(c.656C > T), resulting in a p.(A219V) substitution, in a patient displaying developmental delay, intracranial calcification, and up-regulation of interferon-stimulated gene (ISG) expression in blood. In vitro studies revealed that the STAT2 p.(A219V) variant retained the ability to transduce an IFN-I stimulus. Notably, STAT2 p.(A219V) failed to support receptor desensitization, resulting in sustained STAT2 phosphorylation and ISG up-regulation. Mechanistically, STAT2 p.(A219V) showed defective binding to ubiquitin specific protease 18 (USP18), providing a possible explanation for the chronic IFN-I pathway activation seen in the patient.
Conclusion
Our data indicate an impaired negative regulatory role of STAT2 p.(A219V) in IFN-I signalling and that mutations in STAT2 resulting in a type I interferonopathy state are not limited to the previously reported R148 residue. Indeed, structural modelling highlights at least 3 further residues critical to mediating a STAT2-USP18 interaction, in which mutations might be expected to result in defective negative feedback regulation of IFN-I signalling.</description><identifier>ISSN: 0271-9142</identifier><identifier>EISSN: 1573-2592</identifier><identifier>DOI: 10.1007/s10875-023-01445-3</identifier><identifier>PMID: 36753016</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Antibodies - genetics ; Biochemistry, Molecular Biology ; Biomedical and Life Sciences ; Biomedicine ; Calcification (ectopic) ; Fibrosarcoma ; Gene Expression Regulation ; Genetics ; Genomes ; Genomics ; Homozygote ; Human genetics ; Humans ; Immunofluorescence ; Immunology ; Immunoprecipitation ; Infectious Diseases ; Interferon ; Interferon Type I - genetics ; Internal Medicine ; Life Sciences ; Medical Microbiology ; Mutation ; Mutation - genetics ; Original ; Original Article ; Phosphorylation ; Signal transduction ; Signal Transduction - physiology ; STAT1 Transcription Factor - genetics ; STAT1 Transcription Factor - metabolism ; Stat2 protein ; STAT2 Transcription Factor - chemistry ; STAT2 Transcription Factor - genetics ; Transcriptional Activation ; Ubiquitin ; Ubiquitin Thiolesterase - genetics ; Ubiquitin Thiolesterase - metabolism ; USP18 protein ; Western blotting ; Whole genome sequencing</subject><ispartof>Journal of clinical immunology, 2023-05, Vol.43 (4), p.808-818</ispartof><rights>The Author(s) 2023</rights><rights>2023. The Author(s).</rights><rights>The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Attribution</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-f2204bda9915a59efe4891e72324f270636757a13dbe6a586b258984e95564dd3</citedby><cites>FETCH-LOGICAL-c509t-f2204bda9915a59efe4891e72324f270636757a13dbe6a586b258984e95564dd3</cites><orcidid>0000-0001-7211-7564 ; 0000-0003-4666-5369 ; 0000-0003-1613-6570 ; 0000-0001-8121-0605</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,783,787,888,27936,27937</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36753016$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://cea.hal.science/cea-04334216$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhu, Gaofeng</creatorcontrib><creatorcontrib>Badonyi, Mihaly</creatorcontrib><creatorcontrib>Franklin, Lina</creatorcontrib><creatorcontrib>Seabra, Luis</creatorcontrib><creatorcontrib>Rice, Gillian I.</creatorcontrib><creatorcontrib>Anne-Boland-Auge</creatorcontrib><creatorcontrib>Deleuze, Jean-François</creatorcontrib><creatorcontrib>El-Chehadeh, Salima</creatorcontrib><creatorcontrib>Anheim, Mathieu</creatorcontrib><creatorcontrib>de Saint-Martin, Anne</creatorcontrib><creatorcontrib>Pellegrini, Sandra</creatorcontrib><creatorcontrib>Marsh, Joseph A.</creatorcontrib><creatorcontrib>Crow, Yanick J.</creatorcontrib><creatorcontrib>El-Daher, Marie-Therese</creatorcontrib><title>Type I Interferonopathy due to a Homozygous Loss-of-Inhibitory Function Mutation in STAT2</title><title>Journal of clinical immunology</title><addtitle>J Clin Immunol</addtitle><addtitle>J Clin Immunol</addtitle><description>Purpose
STAT2 is both an effector and negative regulator of type I interferon (IFN-I) signalling. We describe the characterization of a novel homozygous missense STAT2 substitution in a patient with a type I interferonopathy.
Methods
Whole-genome sequencing (WGS) was used to identify the genetic basis of disease in a patient with features of enhanced IFN-I signalling. After stable lentiviral reconstitution of STAT2-null human fibrosarcoma U6A cells with STAT2 wild type or p.(A219V), we performed quantitative polymerase chain reaction, western blotting, immunofluorescence, and co-immunoprecipitation to functionally characterize the p.(A219V) variant.
Results
WGS identified a rare homozygous single nucleotide transition in
STAT2
(c.656C > T), resulting in a p.(A219V) substitution, in a patient displaying developmental delay, intracranial calcification, and up-regulation of interferon-stimulated gene (ISG) expression in blood. In vitro studies revealed that the STAT2 p.(A219V) variant retained the ability to transduce an IFN-I stimulus. Notably, STAT2 p.(A219V) failed to support receptor desensitization, resulting in sustained STAT2 phosphorylation and ISG up-regulation. Mechanistically, STAT2 p.(A219V) showed defective binding to ubiquitin specific protease 18 (USP18), providing a possible explanation for the chronic IFN-I pathway activation seen in the patient.
Conclusion
Our data indicate an impaired negative regulatory role of STAT2 p.(A219V) in IFN-I signalling and that mutations in STAT2 resulting in a type I interferonopathy state are not limited to the previously reported R148 residue. Indeed, structural modelling highlights at least 3 further residues critical to mediating a STAT2-USP18 interaction, in which mutations might be expected to result in defective negative feedback regulation of IFN-I signalling.</description><subject>Antibodies - genetics</subject><subject>Biochemistry, Molecular Biology</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Calcification (ectopic)</subject><subject>Fibrosarcoma</subject><subject>Gene Expression Regulation</subject><subject>Genetics</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Homozygote</subject><subject>Human genetics</subject><subject>Humans</subject><subject>Immunofluorescence</subject><subject>Immunology</subject><subject>Immunoprecipitation</subject><subject>Infectious Diseases</subject><subject>Interferon</subject><subject>Interferon Type I - genetics</subject><subject>Internal Medicine</subject><subject>Life Sciences</subject><subject>Medical Microbiology</subject><subject>Mutation</subject><subject>Mutation - genetics</subject><subject>Original</subject><subject>Original Article</subject><subject>Phosphorylation</subject><subject>Signal transduction</subject><subject>Signal Transduction - physiology</subject><subject>STAT1 Transcription Factor - genetics</subject><subject>STAT1 Transcription Factor - metabolism</subject><subject>Stat2 protein</subject><subject>STAT2 Transcription Factor - chemistry</subject><subject>STAT2 Transcription Factor - genetics</subject><subject>Transcriptional Activation</subject><subject>Ubiquitin</subject><subject>Ubiquitin Thiolesterase - genetics</subject><subject>Ubiquitin Thiolesterase - metabolism</subject><subject>USP18 protein</subject><subject>Western blotting</subject><subject>Whole genome sequencing</subject><issn>0271-9142</issn><issn>1573-2592</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNp9kUtvEzEUhS0EoqHwB1ggS2xgYbh-j1coqiiJFMSCsGBleWY8yVSJHeyZSsOvx-2UAl2wsqX7nXMfB6GXFN5RAP0-U6i0JMA4ASqEJPwRWlCpOWHSsMdoAUxTYqhgZ-hZzlcAwBWTT9EZV1pyoGqBvm-nk8drvA6DT51PMcSTG_YTbkePh4gdXsVj_Dnt4pjxJuZMYkfWYd_X_RDThC_H0Ax9DPjzOLjbTx_w1-1yy56jJ507ZP_i7j1H3y4_bi9WZPPl0_piuSGNBDOQjjEQdeuModJJ4zsvKkO9ZpyJjmlQN7NqR3lbe-VkpWomK1MJb6RUom35Ofow-57G-ujbxochuYM9pf7o0mSj6-2_ldDv7S5eWwqUgtKqOLydHfYPdKvlxjbeWRCcC0bVNS3sm7tuKf4YfR7ssc-NPxxc8OVElmkthDEcZEFfP0Cv4phCuYVlFTBa6QIXis1Uk8p1k-_uJ6Bgb2K2c8y2xGxvY7a8iF79vfO95HeuBeAzkEsp7Hz60_s_tr8A0GOw7w</recordid><startdate>20230501</startdate><enddate>20230501</enddate><creator>Zhu, Gaofeng</creator><creator>Badonyi, Mihaly</creator><creator>Franklin, Lina</creator><creator>Seabra, Luis</creator><creator>Rice, Gillian I.</creator><creator>Anne-Boland-Auge</creator><creator>Deleuze, Jean-François</creator><creator>El-Chehadeh, Salima</creator><creator>Anheim, Mathieu</creator><creator>de Saint-Martin, Anne</creator><creator>Pellegrini, Sandra</creator><creator>Marsh, Joseph A.</creator><creator>Crow, Yanick J.</creator><creator>El-Daher, Marie-Therese</creator><general>Springer US</general><general>Springer Nature B.V</general><general>Springer Verlag</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>1XC</scope><scope>VOOES</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7211-7564</orcidid><orcidid>https://orcid.org/0000-0003-4666-5369</orcidid><orcidid>https://orcid.org/0000-0003-1613-6570</orcidid><orcidid>https://orcid.org/0000-0001-8121-0605</orcidid></search><sort><creationdate>20230501</creationdate><title>Type I Interferonopathy due to a Homozygous Loss-of-Inhibitory Function Mutation in STAT2</title><author>Zhu, Gaofeng ; Badonyi, Mihaly ; Franklin, Lina ; Seabra, Luis ; Rice, Gillian I. ; Anne-Boland-Auge ; Deleuze, Jean-François ; El-Chehadeh, Salima ; Anheim, Mathieu ; de Saint-Martin, Anne ; Pellegrini, Sandra ; Marsh, Joseph A. ; Crow, Yanick J. ; El-Daher, Marie-Therese</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-f2204bda9915a59efe4891e72324f270636757a13dbe6a586b258984e95564dd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Antibodies - genetics</topic><topic>Biochemistry, Molecular Biology</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Calcification (ectopic)</topic><topic>Fibrosarcoma</topic><topic>Gene Expression Regulation</topic><topic>Genetics</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Homozygote</topic><topic>Human genetics</topic><topic>Humans</topic><topic>Immunofluorescence</topic><topic>Immunology</topic><topic>Immunoprecipitation</topic><topic>Infectious Diseases</topic><topic>Interferon</topic><topic>Interferon Type I - genetics</topic><topic>Internal Medicine</topic><topic>Life Sciences</topic><topic>Medical Microbiology</topic><topic>Mutation</topic><topic>Mutation - genetics</topic><topic>Original</topic><topic>Original Article</topic><topic>Phosphorylation</topic><topic>Signal transduction</topic><topic>Signal Transduction - physiology</topic><topic>STAT1 Transcription Factor - genetics</topic><topic>STAT1 Transcription Factor - metabolism</topic><topic>Stat2 protein</topic><topic>STAT2 Transcription Factor - chemistry</topic><topic>STAT2 Transcription Factor - genetics</topic><topic>Transcriptional Activation</topic><topic>Ubiquitin</topic><topic>Ubiquitin Thiolesterase - genetics</topic><topic>Ubiquitin Thiolesterase - metabolism</topic><topic>USP18 protein</topic><topic>Western blotting</topic><topic>Whole genome sequencing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhu, Gaofeng</creatorcontrib><creatorcontrib>Badonyi, Mihaly</creatorcontrib><creatorcontrib>Franklin, Lina</creatorcontrib><creatorcontrib>Seabra, Luis</creatorcontrib><creatorcontrib>Rice, Gillian I.</creatorcontrib><creatorcontrib>Anne-Boland-Auge</creatorcontrib><creatorcontrib>Deleuze, Jean-François</creatorcontrib><creatorcontrib>El-Chehadeh, Salima</creatorcontrib><creatorcontrib>Anheim, Mathieu</creatorcontrib><creatorcontrib>de Saint-Martin, Anne</creatorcontrib><creatorcontrib>Pellegrini, Sandra</creatorcontrib><creatorcontrib>Marsh, Joseph A.</creatorcontrib><creatorcontrib>Crow, Yanick J.</creatorcontrib><creatorcontrib>El-Daher, Marie-Therese</creatorcontrib><collection>Springer_OA刊</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biological Sciences</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of clinical immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhu, Gaofeng</au><au>Badonyi, Mihaly</au><au>Franklin, Lina</au><au>Seabra, Luis</au><au>Rice, Gillian I.</au><au>Anne-Boland-Auge</au><au>Deleuze, Jean-François</au><au>El-Chehadeh, Salima</au><au>Anheim, Mathieu</au><au>de Saint-Martin, Anne</au><au>Pellegrini, Sandra</au><au>Marsh, Joseph A.</au><au>Crow, Yanick J.</au><au>El-Daher, Marie-Therese</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Type I Interferonopathy due to a Homozygous Loss-of-Inhibitory Function Mutation in STAT2</atitle><jtitle>Journal of clinical immunology</jtitle><stitle>J Clin Immunol</stitle><addtitle>J Clin Immunol</addtitle><date>2023-05-01</date><risdate>2023</risdate><volume>43</volume><issue>4</issue><spage>808</spage><epage>818</epage><pages>808-818</pages><issn>0271-9142</issn><eissn>1573-2592</eissn><abstract>Purpose
STAT2 is both an effector and negative regulator of type I interferon (IFN-I) signalling. We describe the characterization of a novel homozygous missense STAT2 substitution in a patient with a type I interferonopathy.
Methods
Whole-genome sequencing (WGS) was used to identify the genetic basis of disease in a patient with features of enhanced IFN-I signalling. After stable lentiviral reconstitution of STAT2-null human fibrosarcoma U6A cells with STAT2 wild type or p.(A219V), we performed quantitative polymerase chain reaction, western blotting, immunofluorescence, and co-immunoprecipitation to functionally characterize the p.(A219V) variant.
Results
WGS identified a rare homozygous single nucleotide transition in
STAT2
(c.656C > T), resulting in a p.(A219V) substitution, in a patient displaying developmental delay, intracranial calcification, and up-regulation of interferon-stimulated gene (ISG) expression in blood. In vitro studies revealed that the STAT2 p.(A219V) variant retained the ability to transduce an IFN-I stimulus. Notably, STAT2 p.(A219V) failed to support receptor desensitization, resulting in sustained STAT2 phosphorylation and ISG up-regulation. Mechanistically, STAT2 p.(A219V) showed defective binding to ubiquitin specific protease 18 (USP18), providing a possible explanation for the chronic IFN-I pathway activation seen in the patient.
Conclusion
Our data indicate an impaired negative regulatory role of STAT2 p.(A219V) in IFN-I signalling and that mutations in STAT2 resulting in a type I interferonopathy state are not limited to the previously reported R148 residue. Indeed, structural modelling highlights at least 3 further residues critical to mediating a STAT2-USP18 interaction, in which mutations might be expected to result in defective negative feedback regulation of IFN-I signalling.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>36753016</pmid><doi>10.1007/s10875-023-01445-3</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-7211-7564</orcidid><orcidid>https://orcid.org/0000-0003-4666-5369</orcidid><orcidid>https://orcid.org/0000-0003-1613-6570</orcidid><orcidid>https://orcid.org/0000-0001-8121-0605</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0271-9142 |
| ispartof | Journal of clinical immunology, 2023-05, Vol.43 (4), p.808-818 |
| issn | 0271-9142 1573-2592 |
| language | eng |
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| source | Springer Link |
| subjects | Antibodies - genetics Biochemistry, Molecular Biology Biomedical and Life Sciences Biomedicine Calcification (ectopic) Fibrosarcoma Gene Expression Regulation Genetics Genomes Genomics Homozygote Human genetics Humans Immunofluorescence Immunology Immunoprecipitation Infectious Diseases Interferon Interferon Type I - genetics Internal Medicine Life Sciences Medical Microbiology Mutation Mutation - genetics Original Original Article Phosphorylation Signal transduction Signal Transduction - physiology STAT1 Transcription Factor - genetics STAT1 Transcription Factor - metabolism Stat2 protein STAT2 Transcription Factor - chemistry STAT2 Transcription Factor - genetics Transcriptional Activation Ubiquitin Ubiquitin Thiolesterase - genetics Ubiquitin Thiolesterase - metabolism USP18 protein Western blotting Whole genome sequencing |
| title | Type I Interferonopathy due to a Homozygous Loss-of-Inhibitory Function Mutation in STAT2 |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-11-14T00%3A46%3A42IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Type%20I%20Interferonopathy%20due%20to%20a%20Homozygous%20Loss-of-Inhibitory%20Function%20Mutation%20in%20STAT2&rft.jtitle=Journal%20of%20clinical%20immunology&rft.au=Zhu,%20Gaofeng&rft.date=2023-05-01&rft.volume=43&rft.issue=4&rft.spage=808&rft.epage=818&rft.pages=808-818&rft.issn=0271-9142&rft.eissn=1573-2592&rft_id=info:doi/10.1007/s10875-023-01445-3&rft_dat=%3Cproquest_pubme%3E2802187277%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c509t-f2204bda9915a59efe4891e72324f270636757a13dbe6a586b258984e95564dd3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2802187277&rft_id=info:pmid/36753016&rfr_iscdi=true |