Clinical relevance of inherited genetic differences in human tryptases: Hereditary alpha-tryptasemia and beyond

Abstract

Objective: To describe our current understanding of hereditary α-tryptasemia (HαT), how HαT fits into the evolutionary context of tryptases and contemporary framework of mast cell-associated disorders, and to discuss the future clinical and therapeutic landscape for symptomatic individuals with HαT.

Data sources: Primary peer-reviewed literature.

Study selections: Basic, clinical, and translational studies describing tryptase gene composition, generation, secretion, and elevation and the associated clinical impacts of HαT and treatment of such individuals were reviewed.

Results: HαT is a common autosomal dominant genetic trait caused by increased TPSAB1 copy number encoding α-tryptase. Approximately 1 in 20 White individuals have HαT, making it by far the most common cause for elevated basal serum tryptase levels. Although many individuals with HαT may not manifest associated symptoms, the prevalence of HαT is increased in patients with clonal and nonclonal mast cell-associated disorders wherein it is linked to more prevalent and/or severe anaphylaxis and increased mast cell mediator-associated symptoms. Increased generation of mature α/β-tryptase heterotetramers, and their unique physiochemical properties, may be responsible for some of these clinical findings.

Conclusion: HαT is a common modifier of mast cell-associated disorders and reactions. Nevertheless, whether HαT may be an independent cause of clinical phenotypes with which it has been associated remains unproven. Correct identification of HαT is critical to accurate interpretation of serum tryptase levels in the clinical evaluation of patients. Beyond HαT, we foresee tryptase genotyping as an important parameter in the standard workup of patients with mast cell-associated disorders and development of therapeutic modalities targeting these patients and associated clinical phenotypes.

Figure 1.. Reported tryptase haplotypes and genotypes in healthy individuals and in those with HαT.

(Left) Reported tryptase haplotypes for secreted alpha- (α) and beta-tryptases (β) arising from TPSAB1 and TPSB2 on chromosome 16 (Chr. 16) p13.3, with associated minor haplotype frequencies (MHF) and variant haplotype frequencies (VHF) in parentheses. (Right) Common tryptase genotypes with reported genotype frequencies (GF).

Figure 2.. Putative effects of mature tryptases in HαT.

Increased TPSAB1 copy number encoding α-tryptase is associated with generation of mature αβ-tryptase heterotetramers. Following mast cell activation and release of secretory granule contents, mature αβ-tryptases can contribute to mast cell degranulation in an autocrine manner through cleavage of the mechanoreceptor EMR2. αβ-Tryptases also selectively cleave and activate PAR2, potentially leading to increased acute vascular permeability and neuroinflammation. Mature β-tryptases have been shown to promote proliferation of connective tissue fibroblasts and airway smooth muscle cells which is associated with extracellular matrix remodeling and fibrosis. In the airways, mature β-tryptases have also been shown to promote smooth muscle tone, potentially in part by cleaving the bronchodilator VIP. *It is currently unknown whether αβ-tryptases have differential effects on connective tissue and airway phenotypes. EMR2, EGF-Like Module-Containing Mucin-Like Hormone Receptor-Like 2; PAR2, protease-activated receptor 2; VIP, vasoactive intestinal peptide; MRGPRX2, Mas-related G protein-coupled receptor-X2; FcεRI, high affinity IgE receptor.