Tryptase haplotype in mastocytosis: Relationship to disease variant and diagnostic utility of total tryptase levels
Introduction
An elevated baseline total tryptase level is a minor diagnostic criterion for systemic mastocytosis according to World Health Organization criteria [1]. Tryptases are serine proteases produced by mast cells [2], [3]. Among members of the tryptase family in humans, including α, β, δ [4], ε [5] and γ (transmembrane) [6], [7], the two that are most abundantly expressed in and secreted by mast cells are α and β tryptases. Tryptases ε and γ are ≤ 50% identical to α and β tryptases, while δ-tryptase, though more closely related to α/β-tryptases, is truncated 40 amino acids shy of the C-terminus of α/β tryptases and appears to be less abundantly expressed [8], [9]. Human mature β tryptase is stored in mast cell granules and released upon activation while α tryptase is apparently processed only to the proenzyme stage and is constitutively secreted from mast cells along with β protryptase [10]. Therefore, serum or plasma levels of mature β tryptase are found transiently elevated after a mast cell degranulation event such as anaphylaxis, while the levels of the precursors of α/β tryptase are reported to reflect the total body mast cell burden; and to be elevated in patients with mastocytosis when compared to the general population [11], [12], [13].
The genes encoding α and β tryptases are located in 2 loci in close proximity to each other on chromosome 16p13.3 [4]. Mapping data suggests that α alleles compete with β alleles at one locus, while an adjacent locus contains β alleles exclusively (αβ versus ββ haplotype) [7]. Accordingly, it has been shown that 20–29% of the normal population lacks α tryptase and has a ββ:ββ genotype [10], [14], [15].
The αβ tryptase haploytpe and female gender are associated with a small but statistically significant elevation of circulating tryptase levels in healthy individuals [16]. It is, however, not known whether patients with mastocytosis have the same allelic distribution of α and β tryptase genes as the general population and whether those lacking the α tryptase gene have a corresponding decrease in circulating tryptase protein levels. The World Health Organization’s (WHO) diagnostic criteria for systemic mastocytosis do not take the α/β tryptase haplotype into account. Because of the potential impact of this haplotype on these criteria, we have examined the α/β tryptase genes in a cohort of patients with mastocytosis and evaluated the correlations of the α/β tryptase genotype with category of disease, serum tryptase levels and hematologic laboratory values.
Section snippets
Patients and methods
Thirty-one patients (13 males) with mastocytosis were examined after signing informed consent. All patients were diagnosed and classified into a disease category according to the World Health Organization’s criteria. The numbers of patients in each disease category in the order of increasing disease severity were as follows: 4 patients with pediatric-onset cutaneous mastocytosis (CM), 24 with indolent systemic mastocytosis (ISM) (9 with the subvariant smoldering systemic mastocytosis [SSM]), 2
Results
Seven of 31 (23%) patients with mastocytosis lacked the α tryptase gene while 8 (26%) patients had 2 α tryptase alleles. This distribution is similar to that of the general population and is consistent with a population in Hardy–Weinberg equilibrium. These results suggest that patients with mastocytosis do not have a skewed distribution of α tryptase alleles.
There was a strong correlation between the severity of mastocytosis category and plasma total, and mature tryptase levels (Spearman’s r
Discussion
Baseline total tryptase levels in mastocytosis are thought to reflect enzymatically inactive α and β protryptases that are constitutively secreted, even though a portion of β-protryptase undergoes intracellular processing to yield mature tryptase and is then stored in secretory granules [2]. Circulating protryptase levels thus appear to reflect the spontaneous secretion of both α and β protryptases, and possibly other tryptase precursors. Our results support the conclusion that while some
Acknowledgments
This work is supported by NIH grants HL024136 (G.H.C. and D.S.) and AI20487 (LBS), and the Division of Intramural Research, NIAID.
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Cited by (38)
Reply
2021, Journal of Allergy and Clinical ImmunologyHereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis
2021, BloodCitation Excerpt :The tryptase locus contains four tryptase encoding genes (TPSG1, TPSB2, TPSAB1, and TPSD1), of which only TPSB2 and TPSAB1 encode the secreted isoforms of tryptase. Although TPSB2 is considered to encode only β-tryptase isoforms, the TPSAB1 locus encodes either α or β isoforms.28,29 In addition to the canonical genotypes (0α:4β, 1α:3β, and 2α:2β) based on isoform expression of 4 tryptase genes at these 2 genetic loci, increased germline TPSAB1 copy number encoding α-tryptase has recently been described as hereditary α-tryptasemia (HαT).28,30
The Utility of Measuring Urinary Metabolites of Mast Cell Mediators in Systemic Mastocytosis and Mast Cell Activation Syndrome
2020, Journal of Allergy and Clinical Immunology: In PracticeDrug hypersensitivity in the fast lane: What clinicians should know about phenotypes, endotypes, and biomarkers
2020, Annals of Allergy, Asthma and ImmunologyCitation Excerpt :Increases above the reference range of 11.4 ng/mL are indicative of acute mast cell or basophil activation or increase in total mast cell number. Furthermore, increases of 2 ng/mL or more plus 1.2 times the baseline are considered significant for patients with a normal baseline tryptase level.33,34 Interestingly, the newly recognized hereditary α-tryptasemia relates to elevated baseline tryptase levels in several members of a family because of the duplication or triplication of α-tryptase genes.
Mast Cell Activation Syndrome: Tools for Diagnosis and Differential Diagnosis
2020, Journal of Allergy and Clinical Immunology: In PracticeCitation Excerpt :The tryptase gene locus, on chromosome 16p13.3, has 4 paralogous genes: TPSG1, TPSB2, TPSAB1, and TPSD1.123,124 Serum tryptase is encoded by 2 of those genes that express the alpha- and beta-isoforms.125-127 Beta-tryptase is encoded by TPSB2.
Therapeutic targeting of cathepsin C: from pathophysiology to treatment
2018, Pharmacology and TherapeuticsCitation Excerpt :Substantial differences in activation sequences between soluble tryptases/mastins and membrane-anchored tryptases suggest that other pathways may be involved. An uncertain but possibly substantial proportion of tryptases released by mast cells are monomeric, catalytically inactive zymogen, which is suspected to be secreted constitutively and to be the form of nearly all immunoreactive tryptase circulating under baseline conditions (Akin et al., 2007; Schwartz et al., 2003). Whether CatC secreted by mast cells or other cell types could process tryptase from this extracellular pool and whether CatC processed monomeric tryptase could form active tetramers in vivo in the absence of granule heparin is presently unclear.
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Currently at the Division of Allergy and Immunology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.