Familial Chilblain Lupus – A Monogenic Form of Cutaneous Lupus Erythematosus due to a Heterozygous Mutation in &lt;i&gt;TREX1&lt;/i&gt;

Günther, Claudia; Meurer, Michael; Stein, Annette; Viehweg, Antje; Lee‐Kirsch, Min Ae

doi:10.1159/000222430

Cited by 54 publications

(21 citation statements)

References 50 publications

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“…Two genes were of particular interest in the dog, the gene for complement subcomponent, C1r, ( C1r ) which is associated with inherited DLE in humans, arthralgia, autoimmune disease, arthritis, mild nephritis, and recurrent rhinobronchitis, and TREX1 , which is associated with Chilblain lupus, another monogenetic form of cutaneous lupus (Day et al 1972; Moncada et al 1972; Rich et al 1979; Gunther et al 2009). C1r maps on CFA 27, and was excluded from major causative association with ECLE based on the GWAS data.…”

Section: Discussionmentioning

confidence: 99%

Familial cutaneous lupus erythematosus (CLE) in the German shorthaired pointer maps to CFA18, a canine orthologue to human CLE

et al. 2010

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A familial form of lupus, termed exfoliative cutaneous lupus erythematosus (ECLE) has been recognized for decades in German shorthaired pointer dogs (GSP). Previous studies were suggestive of autosomal recessive inheritance. The disease presents as a severe dermatitis with age of onset between 16 and 40 weeks, and mirrors cutaneous lupus erythematosus (CLE) in humans. Lameness and, in advanced cases, renal disease may be present. Most affected dogs are euthanized before reaching the age of 4 years. The diagnosis is made by clinical observations and microscopic examination of skin biopsies. In humans, many different forms of CLE exist and various genes and chromosomal locations have been implicated. The large number of potential candidate loci combined with often weak association prevented in depth screening of the dog population thus far. During the course of our studies, we developed a colony of dogs with ECLE as a model for human CLE and the genetic analysis of these dogs confirmed the autosomal recessive mode of inheritance of CLE in GSPs. Using canine patient material, we performed a genome-wide association study (GWAS) to identify the genomic region harboring the gene involved in the development of the disease in GSPs. We identified a SNP allele on canine chromosome 18 that segregated with the disease in the 267 dogs tested. The data generated should allow identification of the mutant gene responsible for this form of cutaneous lupus erythematosus in dogs and assist in the understanding of the development of similar disease in humans.

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Section: Discussionmentioning

confidence: 99%

Familial cutaneous lupus erythematosus (CLE) in the German shorthaired pointer maps to CFA18, a canine orthologue to human CLE

et al. 2010

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“…Gain-of-function mutations of STING (Table 2) have also been linked to the autoimmune disease familial chilblain lupus (FCL) [105, 108], a rare hereditary form of SLE commonly associated with cytoplasmic DNA accumulation in monogenic mutations of exonucleases TREX1 [187, 188] or SAMHD [189] (Figure 5). A recent discovery reports FLC in five members of a four-generation family sharing the same TMEM173 (STING) variant that encodes a single polymorphism of G166E.…”

Section: Sting Related Autoimmunitymentioning

confidence: 99%

Regulating STING in health and disease

Li¹,

Wilson

Kiss-Tóth³

2017

J Inflamm

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The presence of cytosolic double-stranded DNA molecules can trigger multiple innate immune signalling pathways which converge on the activation of an ER-resident innate immune adaptor named “STimulator of INterferon Genes (STING)”. STING has been found to mediate type I interferon response downstream of cyclic dinucleotides and a number of DNA and RNA inducing signalling pathway. In addition to its physiological function, a rapidly increasing body of literature highlights the role for STING in human disease where variants of the STING proteins, as well as dysregulated STING signalling, have been implicated in a number of inflammatory diseases. This review will summarise the recent structural and functional findings of STING, and discuss how STING research has promoted the development of novel therapeutic approaches and experimental tools to improve treatment of tumour and autoimmune diseases.

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“…These patients exhibit a severe phenotype involving the calcification of basal ganglia and white matter in the brain that negatively impacts motor and social development [18–20]. FCL is a dominant form of lupus erythematosus [9, 11, 21], which shares significant phenotypic overlap with AGS including increased levels of interferon alpha and circulating antinuclear antibodies to dsDNA or ssDNA, suggesting a common pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Defects in DNA degradation revealed in crystal structures of TREX1 exonuclease mutations linked to autoimmune disease

Bailey¹,

Harvey²,

Perrino³

et al. 2012

DNA Repair

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Mutations within the human TREX1 3' exonuclease are associated with Aicardi-Goutières Syndrome (AGS) and familial chilblain lupus (FCL). Both AGS and FCL are autoimmune diseases that result in increased levels of interferon alpha and circulating antibodies to DNA. TREX1 is a member of the endoplasmic reticulum (ER)-associated SET complex and participates in granzyme A-mediated cell death to degrade nicked genomic DNA. The loss of TREX1 activity may result in the accumulation of double-stranded DNA (dsDNA) degradation intermediates that trigger autoimmune activation. The X-ray crystal structures of the TREX1 wt apoprotein, the dominant D200H, D200N and D18N homodimer mutants derived from AGS and FCL patients, as well as the recessive V201D homodimer mutant have been determined. The structures of the D200H and D200N mutant proteins reveal the enzyme has lost coordination of one of the active site metals, and the catalytic histidine (H195) is trapped in a conformation pointing away from the active site. The TREX1 D18N and V201D mutants are able to bind both metals in the active site, but with inter-metal distances that are larger than optimal for catalysis. Additionally, all of the mutant structures reveal a reduced mobility in the catalytic histidine, providing further explanation for the loss of catalytic activity. The structures of the mutant TREX1 proteins provide insight into the dysfunction relating to human disease. Additionally, the TREX1 apoprotein structure together with the previously determined wild type substrate and product structures allow us to propose a distinct mechanism for the TREX1 exonuclease.

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Familial Chilblain Lupus – A Monogenic Form of Cutaneous Lupus Erythematosus due to a Heterozygous Mutation in <i>TREX1</i>

Cited by 54 publications

References 50 publications

Familial cutaneous lupus erythematosus (CLE) in the German shorthaired pointer maps to CFA18, a canine orthologue to human CLE

Familial cutaneous lupus erythematosus (CLE) in the German shorthaired pointer maps to CFA18, a canine orthologue to human CLE

Regulating STING in health and disease

Defects in DNA degradation revealed in crystal structures of TREX1 exonuclease mutations linked to autoimmune disease

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