ADAM33

Official Full Name

ADAM metallopeptidase domain 33

Organism

Homo sapiens

GeneID

80332

Background

This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. This protein is a type I transmembrane protein implicated in asthma and bronchial hyperresponsiveness. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2013]

Synonyms

C20orf153; DJ964F7.1;

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Detailed Information

The ADAM33 gene is a member of the superintegration of the integrin-metalloproteinase (ADAM) gene, which consists of eight domains, including signal peptide domain, prodomain, metalloproteinase domain, disintegrin-like domain, cysteine-rich domain, epidermal growth factor domain, transmembrane domain and cytoplasmic domain. ADAM33 molecule has five glycosylation sites, all of which are N-linked glycosylation at the aspartate, two in the precursor domain, two in the catalytic domain, and one in the decomposing domain, human ADAM33 molecule requires glycosylation to be biologically active.

ADAM33 is identified as an asthma susceptibility gene. ADAM protein has biological effects such as cell signal transduction, cell fusion, intercellular adhesion and metalloproteinase activity. Its metalloproteinase activity can cause damage to alveolar tissue structure and affect lung function indicators. ADAM33 is an active protease that activates α2-macroglobulin, an important member of the lung defense system, and is involved in airway obstruction and tissue remodeling. So it is closely related to the physiological processes in which airway inflammatory reactions occur. Despite a certain understanding of the ADAM33 gene function such as conduction signals, activation of cell proliferation, decomposition of extracellular matrix, and increase of fibroblast mobility, but it is still in its infancy.

ADAM33 and Asthma

Bronchial Asthma is a chronic airway inflammation involving mast cells, eosinophils, and T lymphocytes. It not only has bronchial smooth muscle spasm, but also mucosal edema, exudation, and mucosal gland hyperplasia. Airway smooth muscle cells and fibroblasts are involved in airway hyperresponsiveness and airway remodeling. This is consistent with the predominant expression of ADAM33 mRNA in smooth muscle cells, fibroblasts and myofibroblasts. The expression of ADAM33 mRNA in airway remodeling in a mouse model of chronic asthma revealed that repeated allergic stimulation can significantly increase the expression of ADAM33 mRNA in mouse lung tissue, thus indicating that ADAM33 plays an important role in airway remodeling in chronic asthma.

There is a wide-ranging linkage disequilibrium between the SNPs of the ADAM33 gene, and it is not possible to determine which SNP plays a leading role in the development of asthma. The current hypothetical mechanism: (1) ADAM33 may participate in airway remodeling like other MMPs (such as MMP9); (2) ADAM33 can promote membrane-bound growth factors (such as EGF, TGF) and their receptors, stimulating gas Proliferation and differentiation of interstitial cells; (3) ADAM33 may bind to fibroblasts to increase mobility; (4) signaling function of ADAM33 activates signaling pathways for cell proliferation and differentiation; (5) binding to integrin, Affects the interaction between interstitial cells or cells and matrix.

ADAM33 Figure 1. Key cells influenced by ADAM33 in airway remodelling in asthma. (Mahesh, et al. 2013)

ADAM33 and COPD

Chronic obstructive pulmonary disease (COPD) is a long-term, recurrent and preventable respiratory system disease. ADAM33 is the first identified bronchial asthma and airway hyperresponsiveness gene that is selectively expressed in mesenchymal cells and participates in the airway remodeling process throughout the progression of the lesion. Recent studies have shown that the polymorphism of the ADAM33 gene leads to accelerated decline in lung function and impaired lung function. It is found that ADAM33 gene polymorphism is highly correlated with the pathogenesis of COPD and has a significant impact on the number of airway inflammatory cells and lung function.

Single nucleotide polymorphisms (SNPs) refer to the substitution, transformation, etc. of a single base at a particular position in a normal individual or population. Currently, it is widely used in biologically relevant fields such as genetics, drug resistance, and disease susceptibility. Although SNPs are not directly pathogenic, they can make organisms more susceptible to certain pathogenic factors and thus more susceptible to the disease.

The ADAM33 gene is mainly expressed in fibroblasts of smooth muscle cells and lung tissues. It is not expressed in epithelial cells, T lymphocytes and inflammatory cells. This selective expression suggests that its function may be associated with airway remodeling and the progression of the disease. Moreover, airway remodeling also occurs during the progression of chronic obstructive pulmonary disease (COPD). There are more than 55 polymorphic loci in the ADAM33 gene, 8 of which are associated with the risk of COPD. The Q-1 locus single nucleotide polymorphism of the ADAM33 gene is a risk factor for the overall incidence of COPD. The T1 locus of the ADAM33 gene is associated with the risk of COPD, but there may be variability in the ADAM33 gene polymorphism in subjects of different ethnicities and environments, leading to differences in its association with COPD.

Studies have shown that alleles of ADAM33 can increase the incidence of COPD. The meta-analysis by Zhou et al. showed that COPD susceptibility in Asian populations was associated with Q-1, F+1, ST+5, T1, T2 and S1, while T2, Q-1 and ST+ 5 were associated with European populations, suggesting there may be variability in the ADAM33 gene polymorphism in subjects of different ethnicities. The current meta-analysis investigated the association between ADAM33 gene polymorphisms and chronic obstructive pulmonary disease. The results of the study showed that S2 and T1 homozygous carriers did not increase or decrease the risk of chronic obstructive pulmonary disease and had little effect on the treatment of COPD.

References:

Chi, X., Wang, L., Wang, J., Li, Q., Wang, X., & Wang, J., et al. (2013). Association of adam33 gene polymorphisms with asthma in a chinese population. Clinical Respiratory Journal, 7(1), 16.
Tripathi, P., Awasthi, S., & Gao, P. (2014). Adam metallopeptidase domain 33 (adam33): a promising target for asthma. Mediators Inflamm,2014(8), 572025.
Mahesh, P. A. (2013). Unravelling the role of adam 33 in asthma. Indian Journal of Medical Research, 137(3), 447-50.
Xu, Y., & Zhang, J. X. (2015). Adam33 polymorphisms and susceptibility to allergic rhinitis: a meta-analysis. European Archives of Oto-Rhino-Laryngology, 272(3), 597-605.
Howard, T. D., Postma, D. S., Jongepier, H., Moore, W. C., Koppelman, G. H., & Zheng, S. L., et al. (2003). Association of a disintegrin and metalloprotease 33 (adam33), gene with asthma in ethnically diverse populations. Journal of Allergy & Clinical Immunology, 112(4), 717-722.
Saadhussein, A., Thabet, E. H., Taha, M. M., Shahy, E. M., & Mahdyabdallah, H. (2016). Association of adam33 gene polymorphism and arginase activity with susceptibility to ventilatory impairment in wood dust-exposed workers. Human & Experimental Toxicology, 35(9), 966-973.

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