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Clinical & Experimental Allergy

Genetic deficiency of human mast cell a-tryptase

Authors

  • D. Soto,

    1. Cardiovascular Research Institute and Department of Medicine, University of California at San Francisco, San Francisco, California, USA
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  • C. Malmsten,

    1. Cardiovascular Research Institute and Department of Medicine, University of California at San Francisco, San Francisco, California, USA
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  • J. L. Blount,

    1. Cardiovascular Research Institute and Department of Medicine, University of California at San Francisco, San Francisco, California, USA
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  • D. J. Muilenburg,

    1. Cardiovascular Research Institute and Department of Medicine, University of California at San Francisco, San Francisco, California, USA
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  • G. H. Caughey

    1. Cardiovascular Research Institute and Department of Medicine, University of California at San Francisco, San Francisco, California, USA
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George H. Caughey, Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA 94143–0911, USA. E-mail: ghc@itsa.ucsf.edu

Summary

Background Human α- and β-tryptases are proteases secreted by mast cells. Beta (but not α) 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 α-alleles compete with some β-alleles at one locus and that an adjacent locus contains β-alleles exclusively. This hypothesis predicts that β-alleles outnumber α and that some genomes lack α genes altogether.

Methods To test this hypothesis, we developed PCR-based techniques to distinguish α from β genes. We then genotyped genomic DNA from individuals and tryptase-expressing cell lines.

Results In support of our hypothesis, we find that α-tryptase deficiency affects 80/274 (29%) of individuals surveyed. The genotype of the α-deficient individuals is ββββ, due to inheritance of four β genes. The percentage of the population with the mixed genotypes ααββ and αβββ is 21% and 50%, respectively. Accounting for all α- and β-alleles at the tandem loci on 16p13.3, overall α-allele frequency is only 0.23, with β-alleles considerably outnumbering α as hypothesized. In samples of defined ethnicity, α 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 α-genes; thus, lack of α transcripts in these cells is due to absence of α-genes rather than β-selective transcription. By contrast, α-transcribing Mono Mac 6 and KU812 cells contain α- and β-genes.

Conclusions Genetic α-tryptase deficiency is common and varies strikingly between ethnic groups. Because β-tryptases are implicated in allergic disorders, inherited differences in α/β-genotype may affect disease susceptibility, severity and response to tryptase inhibitor therapy.

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