title: Genetic deficiency of human mast cell alpha-tryptase.
abstract: BACKGROUND
  Human alpha- and beta-tryptases are proteases secreted by mast cells. Beta (but not alpha) tryptases are implicated in asthma. Genes encoding both types of tryptases cluster on chromosome 16p13.3.
  
  
  OBJECTIVE
  This study examines the hypothesis, generated from mapping data, that alpha-alleles compete with some beta-alleles at one locus and that an adjacent locus contains beta-alleles exclusively. This hypothesis predicts that beta-alleles outnumber alpha and that some genomes lack alpha genes altogether.
  
  
  METHODS
  To test this hypothesis, we developed PCR-based techniques to distinguish alpha from beta genes. We then genotyped genomic DNA from individuals and tryptase-expressing cell lines.
  
  
  RESULTS
  In support of our hypothesis, we find that alpha-tryptase deficiency affects 80/274 (29%) of individuals surveyed. The genotype of the alpha-deficient individuals is betabetabetabeta, due to inheritance of four beta genes. The percentage of the population with the mixed genotypes alphaalphabetabeta and alphabetabetabeta is 21% and 50%, respectively. Accounting for all alpha- and beta-alleles at the tandem loci on 16p13.3, overall alpha-allele frequency is only 0.23, with beta-alleles considerably outnumbering alpha as hypothesized. In samples of defined ethnicity, alpha deficiency affects 45% of Caucasians, but a much lower percentage of other backgrounds, including African-Americans and Asians. Examination of cell lines reveals that HMC-1 and U-937 lack alpha-genes; thus, lack of alpha transcripts in these cells is due to absence of alpha-genes rather than beta-selective transcription. By contrast, alpha-transcribing Mono Mac 6 and KU812 cells contain alpha- and beta-genes.
  
  
  CONCLUSIONS
  Genetic alpha-tryptase deficiency is common and varies strikingly between ethnic groups. Because beta-tryptases are implicated in allergic disorders, inherited differences in alpha/beta-genotype may affect disease susceptibility, severity and response to tryptase inhibitor therapy.
authors.affiliation: Cardiovascular Research Institute and Department of Medicine, University of California at San Francisco, San Francisco, California 94143-0911, USA.
authors.forename: D
authors.initials: D
authors.lastname: Soto
authors.forename: C
authors.initials: C
authors.lastname: Malmsten
authors.forename: J L
authors.initials: JL
authors.lastname: Blount
authors.forename: D J
authors.initials: DJ
authors.lastname: Muilenburg
authors.forename: G H
authors.initials: GH
authors.lastname: Caughey
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D005838:Genotype; D006801:Humans; D008407:Mast Cells / Q000201:enzymology*; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000032:analysis; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics*; D053802:Tryptases
chemical_list: D012333:RNA, Messenger; D012697:Serine Endopeptidases; D053802:Tryptases