JIA SOON LEN
Have you ever experienced swelling after an insect bite or an allergic reaction to a particular food? Swelling, also known as edema, occurs due to increased permeability of blood vessels, leading to the accumulation of fluid in tissues. In hereditary angioedema (HAE), patients suffer recurrent, localized edemas in subcutaneous or submucosal tissues. Subcutaneous tissue is the deepest layer among the three layers constituting the skin, while submucosal tissue is the layer underneath mucosal tissues. Mucosal tissues line body cavities and are responsible for secreting mucus. HAE is a serious disease with an incidence rate of 1:50000. Many HAE patients experience swelling of the larynx (a component of the respiratory system), which obstructs normal breathing, potentially leading to suffocation.
Within HAE patients, there exists considerable variability in their clinical features. HAE occurs due to the lack of a functional protein called C1 esterase inhibitor (C1-INH), encoded by a gene called SERPING1 found on chromosome 11. One of the primary roles that C1-INH plays in the body is inhibiting molecules known as complement proteases. These complement proteases are enzymes that activate complement proteins to regulate our immune system and cause edemas. The impact of genetic variation in SERPING1 on the structure and function of the encoded C1-INH has not been well-studied previously. To resolve this, Ren and colleagues3 analyzed blood samples from 20 patients using a combination of sequencing, functional analysis, and bioinformatics-based approach in the April issue of The Journal of Allergy and Clinical Immunology.
Two sequencing approaches adopted by Ren and coworkers are whole exome sequencing (WES) and whole genome sequencing (WGS). Our DNA contains four-lettered codes (A, T, C, G) that instruct our body to make proteins; these sequences may also be non-protein encoding. DNA sequences in genes that are transcribed into RNA and remain after splicing are called exons. The genome is the entire set of DNA sequences a cell contains, and the exome is a collective term for all exons in a genome. ‘Whole exome sequencing’ (WES) refers to the technique whereby a researcher sequences all the exons contained in the genome, while ‘whole genome sequencing’ (WGS) involves sequencing the entire genome of an organism.
Through WGS and WES, the authors uncovered several genetic variants in SERPING1. In particular, the study reported novel genetic variants of the SERPING1 gene, such as the single nucleotide variant, F471C. F471C refers to a change in amino acid that DNA encodes for, from phenylalanine to cysteine, at position 471. Our DNA encodes 20 types of amino acids, each with different properties. As such, changing an amino acid to another amino acid that differs greatly in its properties could potentially affect protein structure and function. In the case of the F471C genetic variant, proper folding of the C1-INH is predicted to be hindered which could possibly leading to its degradation, as suggested by Ren et al., who observed that C1-INH protein levels from the F471C genetic variant were very low in the secretions by the cell. Moreover, the authors also identified other SERPING1 gene variants, such as I224S, whereby the patient has the amino acid serine (S) at position 224 instead of isoleucine (I) in the C1-INH protein. While the amount of C1-INH secreted by cells with I224S SERPING1 gene variants was found to be normal, Ren and team noted that the proteins form aggregates, suggesting that the I224S SERPING1 gene variant may also contribute to misfolding of the C1-INH protein.
The findings by Ren et al. are important as they identified novel SERPING1 gene variants and explored their impact on the expression, structure, and function of C1-INH. These insights provided by Ren and coworkers are expected to enhance our understanding of hereditary angioedema’s pathogenesis and thereby aid future treatment decisions.
References
Agostoni, A. et al. Hereditary and acquired angioedema: Problems and progress: Proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. Journal of Allergy and Clinical Immunology 114, S51–S131 (2004).
Hofman, Z. L. M. et al. Angioedema attacks in patients with hereditary angioedema: Local manifestations of a systemic activation process. Journal of Allergy and Clinical Immunology 138, 359–366 (2016).
Ren, Z., Zhao, S., Li, T., Wedner, H. J. & Atkinson, J. P. Insights into the pathogenesis of hereditary angioedema using genetic sequencing and recombinant protein expression analyses. Journal of Allergy and Clinical Immunology 151, 1040-1049.e5 (2023).