Novel TMEM173 Mutation and the Role of Disease Modifying Alleles

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Keskitalo , S , Haapaniemi , E , Einarsdottir , E , Rajamäki , K , Heikkilä , H , Ilander , M , Pöyhönen , M , Morgunova , E , Hokynar , K , Lagström , S , Kivirikko , S , Mustjoki , S , Eklund , K , Saarela , J , Kere , J , Seppänen , M R J , Ranki , A , Hannula-Jouppi , K & Varjosalo , M 2019 , ' Novel TMEM173 Mutation and the Role of Disease Modifying Alleles ' , Frontiers in Immunology , vol. 10 , 2770 . https://doi.org/10.3389/fimmu.2019.02770

Title: Novel TMEM173 Mutation and the Role of Disease Modifying Alleles
Author: Keskitalo, Salla; Haapaniemi, Emma; Einarsdottir, Elisabet; Rajamäki, Kristiina; Heikkilä, Hannele; Ilander, Mette; Pöyhönen, Minna; Morgunova, Ekaterina; Hokynar, Kati; Lagström, Sonja; Kivirikko, Sirpa; Mustjoki, Satu; Eklund, Kari; Saarela, Janna; Kere, Juha; Seppänen, Mikko R. J.; Ranki, Annamari; Hannula-Jouppi, Katariina; Varjosalo, Markku
Contributor organization: Institute of Biotechnology
STEMM - Stem Cells and Metabolism Research Program
Research Programs Unit
Biosciences
Päivi Marjaana Saavalainen / Principal Investigator
Faculty of Medicine
Clinicum
HUS Inflammation Center
Department of Dermatology, Allergology and Venereology
Integrins in immunity
HUS Comprehensive Cancer Center
Department of Clinical Chemistry and Hematology
Department of Oncology
Department of Medical and Clinical Genetics
HUSLAB
Minna Pöyhönen / Principal Investigator
Medicum
Institute for Molecular Medicine Finland
Department of Medicine
Reumatologian yksikkö
Janna Saarela / Principal Investigator
Juha Kere / Principal Investigator
Children's Hospital
HUS Children and Adolescents
Molecular Systems Biology
Date: 2019-12-05
Language: eng
Number of pages: 17
Belongs to series: Frontiers in Immunology
ISSN: 1664-3224
DOI: https://doi.org/10.3389/fimmu.2019.02770
URI: http://hdl.handle.net/10138/309496
Abstract: Upon binding to pathogen or self-derived cytosolic nucleic acids cyclic GMP-AMP synthase (cGAS) triggers the production of cGAMP that further activates transmembrane protein STING. Upon activation STING translocates from ER via Golgi to vesicles. Monogenic STING gain-of-function mutations cause early-onset type I interferonopathy, with disease presentation ranging from fatal vasculopathy to mild chilblain lupus. Molecular mechanisms underlying the variable phenotype-genotype correlation are presently unclear. Here, we report a novel gain-of-function G207E STING mutation causing a distinct phenotype with alopecia, photosensitivity, thyroid dysfunction, and features of STING-associated vasculopathy with onset in infancy (SAVI), such as livedo reticularis, skin vasculitis, nasal septum perforation, facial erythema, and bacterial infections. Polymorphism in TMEM173 and IFIH1 showed variable penetrance in the affected family, implying contribution to varying phenotype spectrum. The G207E mutation constitutively activates inflammation-related pathways in vitro, and causes aberrant interferon signature and inflammasome activation in patient PBMCs. Treatment with Janus kinase 1 and 2 (JAK1/2) inhibitor baricitinib was beneficiary for a vasculitic ulcer, induced hair regrowth and improved overall well-being in one patient. Protein-protein interactions propose impaired cellular trafficking of G207E mutant. These findings reveal the molecular landscape of STING and propose common polymorphisms in TMEM173 and IFIH1 as likely modifiers of the phenotype.
Subject: TMEM173
stimulator of interferon genes
interferon type I
IFIH1
additive effect
protein interactions
OF-FUNCTION MUTATION
AICARDI-GOUTIERES SYNDROME
TUMOR-SUPPRESSOR CYLD
INNATE IMMUNE SENSOR
CYCLIC GMP-AMP
I INTERFERON
STING ACTIVATION
GOLGI TRANSPORT
DI-GMP
3121 General medicine, internal medicine and other clinical medicine
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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