title: Familial chilblain lupus due to a novel mutation in the exonuclease III domain of 3' repair exonuclease 1 (TREX1).
abstract: OBJECTIVE
  Familial chilblain lupus is a rare, autosomal dominant form of lupus erythematosus characterized by cold-induced inflammatory lesions at acral locations presenting in early childhood. Familial chilblain lupus is usually caused by a mutation in TREX1 (3' repair exonuclease 1).
  
  
  METHODS
  We report on a family with dominant chilblain lupus segregating a novel TREX1 mutation (c.585C>G; H195Q) within the highly conserved exonuclease (Exo) III domain. Affected family members experienced cold-induced chilblain lesions of varying degrees, ranging from bluish-red infiltrations to mutilating necrotic ulcerations. In addition, all patients showed signs of systemic disease, such as arthritis, lymphopenia, or antinuclear antibodies. An increased expression of myxovirus resistance protein A in the skin and induction of interferon-stimulated genes in peripheral blood cells demonstrated activation of type I interferon.
  
  
  CONCLUSIONS
  This case further implicates type I interferon-dependent innate immune activation in the pathogenesis of TREX1-associated familial chilblain lupus. Unlike previously reported TREX1 mutations, which affect the Exo I or Exo II domains, the mutation presented here alters the Exo III domain, suggesting a particular role of mutations within the catalytic Exo domains in the pathogenesis of familial chilblain lupus. The high prevalence of extracutaneous manifestations, along with activation of type I interferon, underlines the systemic nature of familial chilblain lupus.
authors.affiliation: Department of Dermatology, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Günther
authors.affiliation: Department of Dermatology, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Berndt
authors.affiliation: Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Wolf
authors.affiliation: Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Min Ae
authors.initials: MA
authors.lastname: Lee-Kirsch
mesh_terms: D000328:Adult; D000368:Aged; D002647:Chilblains / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D005090:Exodeoxyribonucleases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008178:Lupus Erythematosus, Cutaneous / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics*
chemical_list: D010750:Phosphoproteins; D005090:Exodeoxyribonucleases; C035249:exodeoxyribonuclease II; C429526:three prime repair exonuclease 1