Familial Chilblain Lupus - What Can We Learn from Type I Interferonopathies?

ObjectivesFamilial 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.MethodsExome 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-β reporter and Western blotting. IFN signatures in patient blood in response to tofacitinib treatment were measured by RT-PCR of IFN-stimulated genes.ResultsIn 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.ConclusionsA heterozygous gain-of-function mutation in STING can cause familial chilblain lupus. These findings expand the genetic spectrum of type I IFN-dependent disorders and suggest that JAK inhibition may be of therapeutic value.

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Deregulated Type I IFN Response in TREX1-Associated Familial Chilblain Lupus

Journal of Investigative Dermatology ◽

10.1038/jid.2013.496 ◽

2014 ◽

Vol 134 (5) ◽

pp. 1456-1459 ◽

Cited By ~ 23

Author(s):

Katrin Peschke ◽

Franziska Friebe ◽

Nick Zimmermann ◽

Tom Wahlicht ◽

Tina Schumann ◽

...

Keyword(s):

Type I ◽

Type I Ifn ◽

Familial Chilblain Lupus ◽

Chilblain Lupus

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Nucleic acid-mediated autoinflammation and autoimmunity—type I interferonopathies

Journal of Molecular Medicine ◽

10.1007/s00109-016-1467-3 ◽

2016 ◽

Vol 94 (10) ◽

pp. 1081-1084 ◽

Cited By ~ 4

Author(s):

Min Ae Lee-Kirsch ◽

Claudia Günther ◽

Axel Roers

Keyword(s):

Nucleic Acid ◽

Type I ◽

Type I Interferonopathies

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RIG-I-Like Receptors and Type I Interferonopathies

Journal of Interferon & Cytokine Research ◽

10.1089/jir.2016.0095 ◽

2017 ◽

Vol 37 (5) ◽

pp. 207-213 ◽

Cited By ~ 17

Author(s):

Hiroki Kato ◽

Seong-Wook Oh ◽

Takashi Fujita

Keyword(s):

Type I ◽

Type I Interferonopathies

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Therapeutic Approaches to Type I Interferonopathies

Current Rheumatology Reports ◽

10.1007/s11926-018-0743-3 ◽

2018 ◽

Vol 20 (6) ◽

Cited By ~ 4

Author(s):

Marc Bienias ◽

Normi Brück ◽

Constanze Griep ◽

Christine Wolf ◽

Stefanie Kretschmer ◽

...

Keyword(s):

Type I ◽

Therapeutic Approaches ◽

Type I Interferonopathies

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Clinical case of type I interferonopathy: homozygous STAT2 gain-of-function mutation

Pediatric Hematology/Oncology and Immunopathology ◽

10.24287/1726-1708-2021-20-3-132-139 ◽

2021 ◽

Vol 20 (3) ◽

pp. 132-139

Author(s):

А. L. Kozlova ◽

М. Е. Leonteva ◽

V. I. Burlakov ◽

Z. А. Nesterenko ◽

О. М. Laba ◽

...

Keyword(s):

Side Effects ◽

Clinical Case ◽

Kinase Inhibitor ◽

Genetic Defect ◽

Type I ◽

Gain Of Function ◽

The World ◽

Key Aspects ◽

Methods Of Treatment ◽

Type I Interferonopathies

The article is devoted to an extremely rare variant of type I interferonopathies associated with a homozygous gain of function (GOF) mutation in the STAT2 gene in a 5-year-old child. This genetic defect was first described in 2019, and so far only 3 cases are known in the world with a similar pathology. Here we present the fourth clinical case and our experience in managing a patient with STAT2 GOF. The article presents the key aspects of the pathogenesis, clinical picture based on the analysis of all known cases of the disease. The absence of established criteria and methods of treatment for this disease is due to the rarity and relative novelty of the described nosology. We present the experience of treatment using a JAK kinase inhibitor, followed by an assessment of the effectiveness of the therapy and side effects. The patient's parents agreed to use the information, including the child's photo, in scientific research and publications.

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