title: Enho Mutations Causing Low Adropin: A Possible Pathomechanism of MPO-ANCA Associated Lung Injury.
abstract: BACKGROUND
  Myeloperoxidase (MPO) anti-neutrophil cytoplasm autoantibody (ANCA)-associated vasculitis commonly causes life-threatening pulmonary alveolar hemorrhage or fibrosis. Only a limited number of candidate gene variants have been explored, but hitherto, are not widely confirmed. In the present study, we investigated the importance of energy homeostasis associated gene (Enho) mutations and adropin deficiency in the development of MPO-ANCA associated lung injury.
  
  
  METHODS
  We analyzed the peripheral blood mononuclear cells from 152 unrelated patients and 220 population-matched healthy individuals for genetic variations in Enho. Functional studies with adropin knockout (AdrKO) on C57BL/6J mice were also performed.
  
  
  RESULTS
  Sequencing revealed six patients with p.Ser43Thr and that five patients shared Cys56Trp amino acid substitution in Enho. Serum concentration of adropin was significantly lower in patients than that of the healthy subjects (P<0.0001), especially those with Enho mutations. In vivo, homo- and heterozygous carriers of the null adropin allele exhibited MPO-ANCA associated pulmonary alveolar hemorrhage as compared to wild-type mice. AdrKO mice exhibit reduced eNOS (Ser1177) and Akt1 (Ser473) phosphorylation and loss of Treg cells.
  
  
  CONCLUSIONS
  Our findings indicate that the presence of Enho mutations or adropin-deficiency is a probable molecular basis for the initial events triggered in MPO-ANCA associated lung injury.
authors.affiliation: Department of Pathology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Cardiology, Affiliated Union Hospital, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Fang
authors.affiliation: Fujian Provincial Center for Clinical Laboratory, Fujian Provincial Hospital, Fuzhou, Fujian, China.
authors.forename: Falin
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Chengdang
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Analysis, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Pathology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Respiratory, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Lv
authors.affiliation: Department of Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Jinchi
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Qingliang
authors.initials: Q
authors.lastname: He
authors.affiliation: Department of Pharmaceutical Analysis, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Shaohuang
authors.initials: S
authors.lastname: Weng
authors.affiliation: Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Qicai
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Analysis, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Lin
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000097:blood*; D001798:Blood Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D009195:Peroxidase / Q000097:blood*; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000032:analysis / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000378:metabolism; D059467:Transcriptome
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D001798:Blood Proteins; C568440:Enho protein, human; C534289:Enho protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D011506:Proteins; D009195:Peroxidase; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt
keywords: Adropin; Enho mutations; MPO-ANCA associated lung injury; eNOS