Familial chilblain lupus due to a gain-of-function mutation in STING

Autores
König, Nadja; Fiehn, Christoph; Wolf, Christine; Schuster, Max; Cura Costa, Emanuel; Tüngler, Victoria; Alvarez, Hugo Ariel; Chara, Osvaldo; Engel, Kerstin; Goldbach Mansky, Raphaela; Günther, Claudia; Lee Kirsch, Min Ae
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Objectives Familial chilblain lupus is a monogenic form of cutaneous lupus erythematosus caused by loss-of-function mutations in the nucleases TREX1 or SAMHD1. In a family without TREX1 or SAMHD1 mutation, we sought to determine the causative gene and the underlying disease pathology. Methods Exome sequencing was used for disease gene identification. Structural analysis was performed by homology modelling and docking simulations. Type I interferon (IFN) activation was assessed in cells transfected with STING cDNA using an IFN-â reporter and Western blotting. IFN signatures in patient blood in response to tofacitinib treatment were measured by RT-PCR of IFN-stimulated genes. Results In a multigenerational family with five members affected with chilblain lupus, we identified a heterozygous mutation of STING, a signalling molecule in the cytosolic DNA sensing pathway. Structural and functional analyses indicate that mutant STING enhances homodimerisation in the absence of its ligand cGAMP resulting in constitutive type I IFN activation. Treatment of two affected family members with the Janus kinase ( JAK) inhibitor tofacitinib led to a marked suppression of the IFN signature. Conclusions A heterozygous gain-of-function mutation in STING can cause familial chilblain lupus. These findings expand the genetic spectrum of type I IFNdependent disorders and suggest that JAK inhibition may be of therapeutic value.
Fil: König, Nadja. Technische Universität Dresden; Alemania
Fil: Fiehn, Christoph. Acura Akutklinik Für Rheumatologie Baden-baden; Alemania
Fil: Wolf, Christine. Technische Universität Dresden; Alemania
Fil: Schuster, Max. Technische Universität Dresden; Alemania
Fil: Cura Costa, Emanuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina
Fil: Tüngler, Victoria. Technische Universität Dresden; Alemania
Fil: Alvarez, Hugo Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina
Fil: Chara, Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina
Fil: Engel, Kerstin. Technische Universität Dresden; Alemania
Fil: Goldbach Mansky, Raphaela. Technische Universität Dresden; Alemania
Fil: Günther, Claudia. National Institutes of Health; Estados Unidos
Fil: Lee Kirsch, Min Ae. Technische Universität Dresden; Alemania
Materia
Sting
Familial Chilblain Lupus
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/51987
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/51987
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Familial chilblain lupus due to a gain-of-function mutation in STINGKönig, NadjaFiehn, ChristophWolf, ChristineSchuster, MaxCura Costa, EmanuelTüngler, VictoriaAlvarez, Hugo ArielChara, OsvaldoEngel, KerstinGoldbach Mansky, RaphaelaGünther, ClaudiaLee Kirsch, Min AeStingFamilial Chilblain Lupushttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Objectives Familial chilblain lupus is a monogenic form of cutaneous lupus erythematosus caused by loss-of-function mutations in the nucleases TREX1 or SAMHD1. In a family without TREX1 or SAMHD1 mutation, we sought to determine the causative gene and the underlying disease pathology. Methods Exome sequencing was used for disease gene identification. Structural analysis was performed by homology modelling and docking simulations. Type I interferon (IFN) activation was assessed in cells transfected with STING cDNA using an IFN-â reporter and Western blotting. IFN signatures in patient blood in response to tofacitinib treatment were measured by RT-PCR of IFN-stimulated genes. Results In a multigenerational family with five members affected with chilblain lupus, we identified a heterozygous mutation of STING, a signalling molecule in the cytosolic DNA sensing pathway. Structural and functional analyses indicate that mutant STING enhances homodimerisation in the absence of its ligand cGAMP resulting in constitutive type I IFN activation. Treatment of two affected family members with the Janus kinase ( JAK) inhibitor tofacitinib led to a marked suppression of the IFN signature. Conclusions A heterozygous gain-of-function mutation in STING can cause familial chilblain lupus. These findings expand the genetic spectrum of type I IFNdependent disorders and suggest that JAK inhibition may be of therapeutic value.Fil: König, Nadja. Technische Universität Dresden; AlemaniaFil: Fiehn, Christoph. Acura Akutklinik Für Rheumatologie Baden-baden; AlemaniaFil: Wolf, Christine. Technische Universität Dresden; AlemaniaFil: Schuster, Max. Technische Universität Dresden; AlemaniaFil: Cura Costa, Emanuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; ArgentinaFil: Tüngler, Victoria. Technische Universität Dresden; AlemaniaFil: Alvarez, Hugo Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; ArgentinaFil: Chara, Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; ArgentinaFil: Engel, Kerstin. Technische Universität Dresden; AlemaniaFil: Goldbach Mansky, Raphaela. Technische Universität Dresden; AlemaniaFil: Günther, Claudia. National Institutes of Health; Estados UnidosFil: Lee Kirsch, Min Ae. Technische Universität Dresden; AlemaniaB M J Publishing Group2017-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/51987König, Nadja; Fiehn, Christoph; Wolf, Christine; Schuster, Max; Cura Costa, Emanuel; et al.; Familial chilblain lupus due to a gain-of-function mutation in STING; B M J Publishing Group; Annals Of The Rheumatic Diseases; 76; 2; 2-2017; 468-4720003-4967CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://ard.bmj.com/content/76/2/468info:eu-repo/semantics/altIdentifier/doi/10.1136/annrheumdis-2016-209841info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:50:48Zoai:ri.conicet.gov.ar:11336/51987instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:50:48.719CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Familial chilblain lupus due to a gain-of-function mutation in STING
title Familial chilblain lupus due to a gain-of-function mutation in STING
spellingShingle Familial chilblain lupus due to a gain-of-function mutation in STING
König, Nadja
Sting
Familial Chilblain Lupus
title_short Familial chilblain lupus due to a gain-of-function mutation in STING
title_full Familial chilblain lupus due to a gain-of-function mutation in STING
title_fullStr Familial chilblain lupus due to a gain-of-function mutation in STING
title_full_unstemmed Familial chilblain lupus due to a gain-of-function mutation in STING
title_sort Familial chilblain lupus due to a gain-of-function mutation in STING
dc.creator.none.fl_str_mv König, Nadja
Fiehn, Christoph
Wolf, Christine
Schuster, Max
Cura Costa, Emanuel
Tüngler, Victoria
Alvarez, Hugo Ariel
Chara, Osvaldo
Engel, Kerstin
Goldbach Mansky, Raphaela
Günther, Claudia
Lee Kirsch, Min Ae
author König, Nadja
author_facet König, Nadja
Fiehn, Christoph
Wolf, Christine
Schuster, Max
Cura Costa, Emanuel
Tüngler, Victoria
Alvarez, Hugo Ariel
Chara, Osvaldo
Engel, Kerstin
Goldbach Mansky, Raphaela
Günther, Claudia
Lee Kirsch, Min Ae
author_role author
author2 Fiehn, Christoph
Wolf, Christine
Schuster, Max
Cura Costa, Emanuel
Tüngler, Victoria
Alvarez, Hugo Ariel
Chara, Osvaldo
Engel, Kerstin
Goldbach Mansky, Raphaela
Günther, Claudia
Lee Kirsch, Min Ae
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Sting
Familial Chilblain Lupus
topic Sting
Familial Chilblain Lupus
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Objectives Familial chilblain lupus is a monogenic form of cutaneous lupus erythematosus caused by loss-of-function mutations in the nucleases TREX1 or SAMHD1. In a family without TREX1 or SAMHD1 mutation, we sought to determine the causative gene and the underlying disease pathology. Methods Exome sequencing was used for disease gene identification. Structural analysis was performed by homology modelling and docking simulations. Type I interferon (IFN) activation was assessed in cells transfected with STING cDNA using an IFN-â reporter and Western blotting. IFN signatures in patient blood in response to tofacitinib treatment were measured by RT-PCR of IFN-stimulated genes. Results In a multigenerational family with five members affected with chilblain lupus, we identified a heterozygous mutation of STING, a signalling molecule in the cytosolic DNA sensing pathway. Structural and functional analyses indicate that mutant STING enhances homodimerisation in the absence of its ligand cGAMP resulting in constitutive type I IFN activation. Treatment of two affected family members with the Janus kinase ( JAK) inhibitor tofacitinib led to a marked suppression of the IFN signature. Conclusions A heterozygous gain-of-function mutation in STING can cause familial chilblain lupus. These findings expand the genetic spectrum of type I IFNdependent disorders and suggest that JAK inhibition may be of therapeutic value.
Fil: König, Nadja. Technische Universität Dresden; Alemania
Fil: Fiehn, Christoph. Acura Akutklinik Für Rheumatologie Baden-baden; Alemania
Fil: Wolf, Christine. Technische Universität Dresden; Alemania
Fil: Schuster, Max. Technische Universität Dresden; Alemania
Fil: Cura Costa, Emanuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina
Fil: Tüngler, Victoria. Technische Universität Dresden; Alemania
Fil: Alvarez, Hugo Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina
Fil: Chara, Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina
Fil: Engel, Kerstin. Technische Universität Dresden; Alemania
Fil: Goldbach Mansky, Raphaela. Technische Universität Dresden; Alemania
Fil: Günther, Claudia. National Institutes of Health; Estados Unidos
Fil: Lee Kirsch, Min Ae. Technische Universität Dresden; Alemania
description Objectives Familial chilblain lupus is a monogenic form of cutaneous lupus erythematosus caused by loss-of-function mutations in the nucleases TREX1 or SAMHD1. In a family without TREX1 or SAMHD1 mutation, we sought to determine the causative gene and the underlying disease pathology. Methods Exome sequencing was used for disease gene identification. Structural analysis was performed by homology modelling and docking simulations. Type I interferon (IFN) activation was assessed in cells transfected with STING cDNA using an IFN-â reporter and Western blotting. IFN signatures in patient blood in response to tofacitinib treatment were measured by RT-PCR of IFN-stimulated genes. Results In a multigenerational family with five members affected with chilblain lupus, we identified a heterozygous mutation of STING, a signalling molecule in the cytosolic DNA sensing pathway. Structural and functional analyses indicate that mutant STING enhances homodimerisation in the absence of its ligand cGAMP resulting in constitutive type I IFN activation. Treatment of two affected family members with the Janus kinase ( JAK) inhibitor tofacitinib led to a marked suppression of the IFN signature. Conclusions A heterozygous gain-of-function mutation in STING can cause familial chilblain lupus. These findings expand the genetic spectrum of type I IFNdependent disorders and suggest that JAK inhibition may be of therapeutic value.
publishDate 2017
dc.date.none.fl_str_mv 2017-02
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/51987
König, Nadja; Fiehn, Christoph; Wolf, Christine; Schuster, Max; Cura Costa, Emanuel; et al.; Familial chilblain lupus due to a gain-of-function mutation in STING; B M J Publishing Group; Annals Of The Rheumatic Diseases; 76; 2; 2-2017; 468-472
0003-4967
CONICET Digital
CONICET
url http://hdl.handle.net/11336/51987
identifier_str_mv König, Nadja; Fiehn, Christoph; Wolf, Christine; Schuster, Max; Cura Costa, Emanuel; et al.; Familial chilblain lupus due to a gain-of-function mutation in STING; B M J Publishing Group; Annals Of The Rheumatic Diseases; 76; 2; 2-2017; 468-472
0003-4967
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://ard.bmj.com/content/76/2/468
info:eu-repo/semantics/altIdentifier/doi/10.1136/annrheumdis-2016-209841
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv B M J Publishing Group
publisher.none.fl_str_mv B M J Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.13397

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