title: DcR3 mutations in patients with juvenile-onset systemic lupus erythematosus lead to enhanced lymphocyte proliferation.
abstract: OBJECTIVE
  Previous studies suggested a role for the death decoy receptor 3 (DcR3) in the pathogenesis of adult systemic lupus erythematosus (SLE). We investigated the role of DcR3 in juvenile-onset SLE, to identify polymorphisms that might alter the function of this protein.
  
  
  METHODS
  DcR3 was measured in the serum of 61 patients with juvenile SLE. The coding region of the DcR3 gene was sequenced in 100 juvenile and 103 adult patients with SLE, together with 500 healthy controls.
  
  
  RESULTS
  DcR3 was elevated in the serum of juvenile patients with active SLE disease (440.8 ± 169.1 pg/ml), compared to patients with inactive disease (122.6 ± 28.05 pg/ml; p = 0.0014) and controls (69.27 ± 20.23 pg/ml; p = 0.0009). DNA sequencing identified 2 novel missense mutations: c.C167T (p.T56I) in an adult SLE patient and c.C364T (p.H122Y) in a juvenile patient. Recombinant proteins containing these mutations exhibited altered binding kinetics to FasL and they significantly increased lymphocyte proliferation, compared to the wild-type protein (p < 0.05). The adult patient with SLE carrying the p.T56I mutation had significantly increased lymphocyte proliferation compared to 3 SLE controls matched for age, sex, and disease severity.
  
  
  CONCLUSIONS
  DcR3 may play an etiologic role in SLE through either elevated serum levels of wild-type DcR3 or normal levels of gain-of-function DcR3 proteins that increase lymphocyte proliferation.
authors.affiliation: Interdepartment of Biomedical Sciences, Faculty of Graduate School, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Chayanin
authors.initials: C
authors.lastname: Chokdeemeeboon
authors.forename: Pramuk
authors.initials: P
authors.lastname: Ammarinthnukrowh
authors.forename: Siraprapa
authors.initials: S
authors.lastname: Tongkobpetch
authors.forename: Chalurmpon
authors.initials: C
authors.lastname: Srichomtong
authors.forename: Tawatchai
authors.initials: T
authors.lastname: Deekajorndech
authors.forename: Pornpimol
authors.initials: P
authors.lastname: Rianthavorn
authors.forename: Pornchai
authors.initials: P
authors.lastname: Kingwattanakul
authors.forename: Yingyos
authors.initials: Y
authors.lastname: Avihingsanon
authors.forename: Helen L
authors.initials: HL
authors.lastname: Wright
authors.forename: Piyaporn
authors.initials: P
authors.lastname: Akkahat
authors.forename: Voravee P
authors.initials: VP
authors.lastname: Hoven
authors.forename: Wanwimon
authors.initials: W
authors.lastname: Mekboonsonglarp
authors.forename: Steven W
authors.initials: SW
authors.lastname: Edwards
authors.forename: Nattiya
authors.initials: N
authors.lastname: Hirankarn
authors.forename: Kanya
authors.initials: K
authors.lastname: Suphapeetiporn
authors.forename: Vorasuk
authors.initials: V
authors.lastname: Shotelersuk
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D017668:Age of Onset; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D049109:Cell Proliferation; D002648:Child; D018450:Disease Progression; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000473:pathology; D008214:Lymphocytes / Q000473:pathology*; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D053323:Receptors, Tumor Necrosis Factor, Member 6b / Q000235:genetics*; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D053323:Receptors, Tumor Necrosis Factor, Member 6b; C505911:TNFRSF6B protein, human
keywords: AFFINITY; APOPTOSIS; DEATH DECOY RECEPTOR 3; PROLIFERATION; SYSTEMIC LUPUS ERYTHEMATOSUS