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. 2009 Nov;124(5):1099-105.e1-4.
doi: 10.1016/j.jaci.2009.07.026. Epub 2009 Sep 12.

Human Subjects Are Protected From Mast Cell Tryptase Deficiency Despite Frequent Inheritance of Loss-Of-Function Mutations

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Free PMC article

Human Subjects Are Protected From Mast Cell Tryptase Deficiency Despite Frequent Inheritance of Loss-Of-Function Mutations

Neil N Trivedi et al. J Allergy Clin Immunol. .
Free PMC article

Abstract

Background: Mast cell tryptases have proposed roles in allergic inflammation and host defense against infection. Tryptase gene loci TPSAB1 and TPSB2 are known to be polymorphic, but the nature and extent of diversity at these loci have not been fully explored.

Objective: We sought to compare functional and nonfunctional tryptase allele frequencies and establish haplotypes in human populations.

Methods: Tryptase allele frequencies were determined by means of direct sequencing in 270 individuals from HapMap populations of European, African, Chinese, and Japanese ancestry. Haplotypes were predicted, validated in parent-child trios, and compared between populations.

Results: We identify a new frame-shifted tryptase allele (betaIII(FS)) carried by 23% and 19% of individuals of European and African ancestry but 0% of Asian subjects. Homology models predict that betaIII(FS) is functionless. Our genotyping assay shows that allele and haplotype distributions in each population are unique. Strong linkage disequilibrium between TPSAB1 and TPSB2 (r(2)=0.83, D'=0.85) yields 2 major and 5 minor tryptase haplotypes.

Conclusions: Tryptase deficiency alleles (alpha and the newly discovered betaIII(FS)) are common, causing the number of inherited active genes to range from a minimum of 2 to a maximum of 4, with major differences between populations in the proportion of individuals inheriting 2 versus 4 active alleles. African and Asian populations are especially enriched in genes encoding functional and nonfunctional tryptases, respectively. Strong linkage of TPSAB1 and TPSB2 and pairing of deficiency alleles with functional alleles in observed haplotypes protect human subjects from "knockout" genomes and indeed from inheritance of fewer than 2 active alleles.

Figures

FIG 1
FIG 1
The tryptase gene cluster on chromosome 16p13.3. TPSG1, which encodes transmembrane tryptase γ, anchors the telomeric end. At adjacent TPSB2, βII and βIII tryptase genes compete as alleles. Similarly, α and βI genes compete as alleles at adjacent locus TPSAB1. TPSD1 is the δ locus, which encodes a truncated, largely inactive peptidase. Arrows depict transcriptional orientation.
FIG 2
FIG 2
Alignment of frame-shifted and full-length βIII tryptases. The Panel A chromatogram identifies the cytosine insertion (arrow) in βIIIFS. Red, blue, black, and green signify thymine, cytosine, guanine, and adenine, respectively. Panel B compares amino acid sequence of βIIIFS and full-length βIII: −, identical residue; #, conserved "catalytic triad" residue; %, conserved "specificity triad" residue; +, N-glycosylation site. The arrow identifies the residue whose codon contains the frame-shifting insertion. Mature enzyme begins with residue 1.
FIG 3
FIG 3
Models of full-length and frame-shifted βIII tryptases. Full-length (A and C) and frame-shifted (B and D) models are shown with “specificity triad” Asp188, Gly215, and Gly225 in green, catalytic Ser195 in red, and N-glycosylation sites Asn102 and Asn203 in cyan. Residues truncated in βIIIFS are ball and stick models in panel B. Blue, pink, grey, and orange residues, respectively, identify monomers 1–4 of the tryptase tetramer.
FIG 4
FIG 4
Tryptase allele frequencies in HapMap project populations from Yoruba in Ibadan Nigeria (African), Centre d’Etude du Polymorphisme Humain collection from Utah (European), Beijing Han (Chinese), and Tokyo Japanese. Overall allele frequencies are from pooled populations. Large and small brackets mark functional and dysfunctional alleles, respectively.
FIG 5
FIG 5
Tryptase haplotype frequencies in four populations. Haplotypes with overall frequency ≥ 0.15 and < 0.15 are defined as major and minor, respectively.
FIG 6
FIG 6
Active tryptase gene dosage in four populations. *, **, *** represent P values < 0.05, < 0.001, and < 0.0001, respectively.

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