Genetic deficiency of human mast cell a‐tryptase

Soto, Darya; Malmsten, C.; Blount, John L.; Muilenburg, Diego J.; Caughey, George H.

doi:10.1046/j.1365-2222.2002.01416.x

Cited by 79 publications

(73 citation statements)

References 23 publications

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“…The current study shows the difference in median total tryptase levels in the plasma of subjects with (5.2 ng/ml) and without (4.7 ng/ml) the ␣-tryptase gene is small and is not statistically significant. If each haploid genome contains either one ␣-tryptase and one ␤-tryptase gene, or two ␤-tryptase genes, as postulated (16), then subjects with four ␤-tryptase genes in their diploid genomes produce almost the same levels of total plasma tryptase as do the combined groups with either two ␤-tryptase and two ␣-tryptase, or three ␤-tryptase and one ␣-tryptase genes. However, whether a difference might have been appreciated if the latter two groups had been identified and separately analyzed was not directly assessed by the current study.…”

Section: Discussionmentioning

confidence: 94%

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Tryptase Precursors Are Preferentially and Spontaneously Released, Whereas Mature Tryptase Is Retained by HMC-1 Cells, Mono-Mac-6 Cells, and Human Skin-Derived Mast Cells

Schwartz

Min

Ren

et al. 2003

The Journal of Immunology

105

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Tryptase (α and β) levels in serum are used to assess mast cell involvement in human disease. Using cultured cells, the current study examines the hypothesis that protryptase(s) are spontaneously secreted by mast cells at rest, whereas mature tryptase(s) are stored in secretory granules until their release by activated cells. HMC-1 cells have only β-tryptase genes and the corresponding mRNA. Mono-Mac-6 cells have both α- and β-tryptase genes but preferentially express α-tryptase. Mono-Mac-6 cells spontaneously secrete most of their tryptase, which consists of α-protryptase, whereas mature tryptase is retained inside these cells. HMC-1 cells also spontaneously secrete most of their tryptase, identified as β-protryptase, and retain mature tryptase. Skin-derived mast cells retain most of their tryptase, which is mature, and spontaneously secrete protryptase(s). Total tryptase levels in plasma are detectable but no different in healthy subjects with and without the gene for α-tryptase, consistent with pro forms of both α- and β-tryptase being spontaneously secreted. Thus, protryptase(s) are spontaneously secreted by resting mast cells, whereas mature tryptase is retained by mast cells until they are activated to degranulate.

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Section: Discussionmentioning

confidence: 94%

“…Approximately 25% of individuals lack a gene for ␣-tryptase (15,16). Whether such a genetic difference affects the level of tryptase in the blood has not been determined.…”

mentioning

confidence: 99%

Tryptase Precursors Are Preferentially and Spontaneously Released, Whereas Mature Tryptase Is Retained by HMC-1 Cells, Mono-Mac-6 Cells, and Human Skin-Derived Mast Cells

Schwartz

Min

Ren

et al. 2003

The Journal of Immunology

105

View full text Add to dashboard Cite

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“…This clone is part of a contig localizing to chromosome 16p, the same chromosomal arm containing ␣-tryptase (TPS1), ␤-tryptases (e.g. TPSB1), ␥-tryptase (TPSG1), and testisin (PRSS21) genes (7,9,10,18,29). The pancreasin gene appears to reside on the centromeric side of the tryptase locus and on the telomeric side of the testisin locus (i.e.…”

Section: Resultsmentioning

confidence: 99%

Structure and Activity of Human Pancreasin, a Novel Tryptic Serine Peptidase Expressed Primarily by the Pancreas

Bhagwandin

Hau

Clair

et al. 2003

Journal of Biological Chemistry

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In a search for genes encoding the serine peptidases prostasin and testisin, which are expressed mainly in prostate and testis, respectively, we identified a related, novel gene. Sequencing of cDNA allowed us to deduce the full amino acid sequence of the human gene product, which we term "pancreasin" because it is transcribed strongly in the pancreas. The idiosyncratic 6-exon organization of the gene is shared by a small group of tryptic proteases, including prostasin, testisin, and ␥-tryptase. Like the other genes, the pancreasin gene resides on chromosome 16p. Pancreasin cDNA predicts a 290-residue, N-glycosylated, serine peptidase with a typical signal peptide, a 12-residue activation peptide cleaved by tryptic hydrolysis, and a 256-amino acid catalytic domain. Unlike prostasin and other close relatives, human pancreasin and a nearly identical chimpanzee homologue lack a carboxyl-terminal membrane anchor, although this is present in 328-residue mouse pancreasin, the cDNA of which we also cloned and sequenced. In marked contrast to prostasin, which is 43% identical in the catalytic domain, human pancreasin is transcribed strongly in pancreas (and in the pancreatic ductal adenocarcinoma line, HPAC) but weakly or not at all in kidney and prostate. Antibodies raised against pancreasin detect cytoplasmic expression in HPAC cells. Recombinant, epitope-tagged pancreasin expressed in Chinese hamster ovary cells is glycosylated and secreted as an active tryptic peptidase. Pancreasin's preferences for hydrolysis of extended peptide substrates feature a strong preference for P1 Arg and differ from those of trypsin. Pancreasin is inhibited by benzamidine and leupeptin but resists several classic inhibitors of trypsin. Thus, pancreasin is a secreted, tryptic serine protease of the pancreas with novel physical and enzymatic properties. These studies provide a rationale for exploring the natural targets and roles of this enzyme.

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“…Although Prss34 is expressed by interleukin (IL) 3-differentiated mouse bone marrow-derived MCs (mBMMCs), it remains to be seen whether tissue MCs express this tryptase. The syntenic human tryptase locus resides ϳ1.2 megabases from the telomeric end of chromosome 16p13.3 (17)(18)(19)(20). This region has been difficult to sequence because of its high rate of mutation and recombination (21).…”

Section: Mc-restricted Granule Proteases and Proteoglycansmentioning

confidence: 99%

Mast Cell-restricted Tryptases: Structure and Function in Inflammation and Pathogen Defense

McNeil

Adachi

Stevens

2007

Journal of Biological Chemistry

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Mast cells (MCs) are highly specialized immune cells present in mammals and in lower organisms that predate the development of adaptive immunity. The strong evolutionary pressure to retain MCs for >500 million years suggests critical roles for these cells in our survival. In support of this conclusion, no human has been identified to date that lacks MCs, despite the adverse roles of MCs in systemic anaphylaxis and varied inflammatory disorders. MCs express numerous lineage-restricted neutral proteases, and four members of the chromosome 17A3.3 family of tryptases are preferentially expressed in mouse MCs. The anatomical location of MCs at host-environment interfaces has raised the possibility that some of these enzymes are evolutionally conserved because they are needed for combating infectious organisms. Here we review recent insights into the structure and function of MC tryptases in inflammation and host defense against bacteria and other infectious organisms. MC-restricted Granule Proteases and ProteoglycansA characteristic morphologic feature of mammalian mast cells (MCs) 3 is their electron-dense secretory granules, which contain serglycin proteoglycans (1, 2) bearing heparin (for review see Ref. 3) and chondroitin sulfates diB and E (4, 5). Heparin is the most negatively charged molecule in the body, and each rat and mouse peritoneal MC contains ϳ25 pg of this glycosaminoglycan, thereby explaining the avidity of MCs for cationic dyes (6). The repeating Ser-Gly sequence in serglycin where its glycosaminoglycans are attached cannot be cleaved by any known protease. This protease resistance feature is biologically relevant because the primary function of serglycin proteoglycans in MCs is to provide a scaffold for formation of macromolecular complexes with the cell's varied granule proteases. When properly folded, a positively charged face forms on the surface of each granule protease that allows it to bind tightly to the proteoglycan's negatively charged glycosaminoglycans (7-9).The proteases packaged in the secretory granules of mouse MCs include carboxypeptidase A3 (CPA3), granzyme B, cathepsin G, neuropsin, transmembrane tryptase/tryptase ␥/protease serine member S (Prss) 31, mouse MC protease (mMCP) 1-10, and mMCP-11/Prss34. Definitive evidence of the importance of heparin-containing serglycin proteoglycans in the packaging of specific cassettes of proteases in the MC's granules came with the characterization of N-deacetylase/Nsulfotransferase-2 (NDST-2)-null mice (10, 11). NDST-2 is essential for heparin biosynthesis and is preferentially expressed in MCs. Because of the loss of fully sulfated heparin, the MCs in the skin and peritoneal cavities of NDST-2-null mice store reduced amounts of mMCP-6 and almost no CPA3, mMCP-4, and mMCP-5, even though all four MC-restricted protease genes are transcribed at normal rates. The accumulated data led to the current view that serglycin proteoglycans are essential for the post-translational processing and granule accumulation of most, if not all, proteases stor...

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Genetic deficiency of human mast cell a‐tryptase

Abstract: 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.

Cited by 79 publications

References 23 publications

Tryptase Precursors Are Preferentially and Spontaneously Released, Whereas Mature Tryptase Is Retained by HMC-1 Cells, Mono-Mac-6 Cells, and Human Skin-Derived Mast Cells

Tryptase Precursors Are Preferentially and Spontaneously Released, Whereas Mature Tryptase Is Retained by HMC-1 Cells, Mono-Mac-6 Cells, and Human Skin-Derived Mast Cells

Structure and Activity of Human Pancreasin, a Novel Tryptic Serine Peptidase Expressed Primarily by the Pancreas

Mast Cell-restricted Tryptases: Structure and Function in Inflammation and Pathogen Defense

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