title: C1 inhibitor gene expression in patients with hereditary angioedema: quantitative evaluation by means of real-time RT-PCR.
abstract: BACKGROUND
  Hereditary angioedema (HAE) is caused by heterozygous defects in the C1 inhibitor (C1-INH) gene (SERPING1/C1NH). In patients' plasma C1-INH levels range between 5% and 30% of normal levels (ie, far from the 50% expected for an autosomal dominant defect). Most patients have antigenic and functional deficiency (type I HAE), and 15% have reduced C1-INH function but normal to increased antigen because of the presence of a dysfunctional protein (type II HAE).
  
  
  OBJECTIVE
  We sought to contribute to the understanding of the pattern of C1-INH gene expression in patients with HAE.
  
  
  METHODS
  We used real-time quantitative RT-PCR to measure C1-INH mRNA levels in PBMCs of 57 patients with HAE typed for mutations in the SERPING1/C1NH gene.
  
  
  RESULTS
  Thirty-six different mutations were identified in genomic DNA. Compared with healthy control subjects, C1-INH mRNA was significantly and similarly reduced in patients with type I and type II HAE (40% and 47%, respectively; P <.0001). By means of direct sequencing of cDNAs, we found that 74% of patients with type I HAE carrying small mutations presented significant amounts of mutated transcripts at the mRNA level, suggesting that both allelic mRNA products were reduced to approximately 50%. In 4 patients carrying large deletions expected to fully inactivate expression from the mutant allele, C1-INH mRNA was 23% on average compared with that seen in control subjects, confirming that normal mRNA was strongly underexpressed.
  
  
  CONCLUSIONS
  These new findings, combined with previous evidence of increased C1-INH consumption, might explain the plasma levels of normal C1-INH that are markedly less than the expected 50%.
authors.affiliation: Department of Internal Medicine, University of Milan, Ospedale S. Giuseppe, 20123 Milan, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Pappalardo
authors.forename: Lorenza C
authors.initials: LC
authors.lastname: Zingale
authors.forename: Marco
authors.initials: M
authors.lastname: Cicardi
mesh_terms: D000799:Angioedema / Q000235:genetics / Q000378:metabolism*; D003174:Complement C1 Inactivator Proteins / Q000235:genetics* / Q000378:metabolism*; D050718:Complement C1 Inhibitor Protein; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods*; D019914:Taq Polymerase
chemical_list: D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein; D012333:RNA, Messenger; D019914:Taq Polymerase