COVID-19 research

Gene: TMPRSS2

Preprint: Vishnubhotla et al. 2020 - https://doi.org/10.1101/2020.06.30.179663
Report a variant rs12329760 (p.V160M) which decreased TMPRSS2 stability. Molecular dynamics and simulation studies demonstrated structural deformation of the mutant protein due to a complete shift in the motif. It can be anticipated that a decrease in TMPRSS2 protein stability could impede viral entry; however, whether this genetic variant has any physiological role on SARS-CoV-2 infection is yet to be determined.
Authors also demonstrate the structural interactions between TMPRSS2 and S2 subunit of SARS-CoV-2 spike protein. Binding to the active site of TMPRSS2 with high precision and specificity was also shown for several protease inhibitors (Camostat, Nafamostat, Upamostat and Bromhexine hydrochloride), which may serve a potential therapeutic benefit (added treatable tag).

Created: 29 Jul 2020, 11:51 a.m. | Last Modified: 29 Jul 2020, 11:51 a.m.

Panel Version: 1.62

Preprint: Gupta et al https://doi.org/10.1101/2020.05.15.098616 Using the Viral Integrated Structural Evolution Dynamic Database and population genomic databases they identified 47 potential functional missense variants within ACE2/SLC6A19/TMPRSS2, warranting genomic enrichment analyses in SARS-CoV-2 patients.

Created: 22 May 2020, 11:02 a.m. | Last Modified: 22 May 2020, 11:02 a.m.

Panel Version: 0.304

Publications

• https://doi.org/10.1101/2020.05.15.098616

Preprint https://doi.org/10.1101/2020.05.04.075911 reports rs35074065 of TMPRSS2 results in the overexpression of both TMPRSS2 and a nearby gene MX1. rs35074065 overlaps with a transcription factor binding site of an activator (IRF1) and a repressor (IRF2). IRF1 activator can bind to variant delC allele, but IRF2 repressor fails to bind. Thus, in an individual carrying the delC allele of rs35074065, there is only activation, but no repression. On viral entry, IRF1 mediated upregulation of MX1 leads to neutrophil infiltration and processing of 614G variant viral Spike protein by neutrophil Elastase. The simultaneous processing of 614G spike protein by TMPRSS2 and Elastase serine proteases facilitates the entry of the 614G subtype into host cells. Thus, SARS-CoV-2, particularly the 614G subtype, has spread more easily and with higher frequency to Europe and North America where the delC allele regulating expression of TMPRSS2 and MX1 host proteins is common, but not to East Asia where this allele is rare.

Created: 11 May 2020, 2:35 p.m. | Last Modified: 12 May 2020, 10:22 a.m.

Panel Version: 0.214

Publications

• https://doi.org/10.1101/2020.05.04.075911

Green List (high evidence)

Appropriate to consider in research panel given known roles in SARS-CoV-2 pathogenesis

Created: 7 May 2020, 1:51 p.m. | Last Modified: 7 May 2020, 1:51 p.m.

Panel Version: 0.203

Mode of inheritance
Unknown

Preprint http://biorxiv.org/cgi/content/short/2020.04.23.057190 analysed coding region variants in TMPRSS2 and the eQTL variants which may affect gene experssion. They suggest that lung-specific eQTL variants may confer different susceptibility or response to SARS-CoV-2 infection from different populations. In particular, we found that the regulatory region variant rs35074065 is associated with high expression of TMPRSS2 (but lower expression of MX1).

Created: 28 Apr 2020, 3:31 p.m. | Last Modified: 28 Apr 2020, 3:31 p.m.

Panel Version: 0.165

Preprint https://www.biorxiv.org/content/10.1101/2020.04.24.056259v2 suggests that ACE2 and TMPRSS2 co-expression in the prostate may explain sex differences in the observed COVID-19 disaparities.

Created: 28 Apr 2020, 2:30 p.m. | Last Modified: 28 Apr 2020, 2:30 p.m.

Panel Version: 0.165

Preprint https://www.medrxiv.org/content/10.1101/2020.04.22.20074963v1 Lopera et al shows a LACK of association between genetic variants at ACE2 and TMPRSS2 and human quantitative phenotypes. The authors recognise that the SARS-CoV-2 virus uses ACE2 for cell invasion, and the serine protease TMPRSS2 for S protein priming and therefore they investigated whether genetic variation in these two genes modulates an individual's genetic predisposition to infection and virus clearance. They examined 178 quantitative phenotypes in relation to 1,273 genetic variants located in or near ACE2 and TMPRSS2: none reached the threshold for significance though these variants may play a role in diseases such as hypertension and chronic inflammation that are often observed in the more severe COVID-19 cases.

Created: 27 Apr 2020, 12:55 p.m. | Last Modified: 27 Apr 2020, 12:55 p.m.

Panel Version: 0.163

Comment on list classification: Updated rating from Amber to Green on this research panel: Known mechanisms for involvement in viral infection (including proteolytic cleavage of the viral receptor, ACE2) plus variants identified in preprints as candidates for COVID-19 severity.

Created: 23 Apr 2020, 4:20 p.m. | Last Modified: 23 Apr 2020, 4:20 p.m.

Panel Version: 0.148

TMPRSS2 present in the UniProt COVID portal: https://covid-19.uniprot.org/uniprotkb/O15393. Facilitates human coronaviruses SARS-CoV and SARS-CoV-2 infections via two independent mechanisms, proteolytic cleavage of ACE2 receptor which promotes viral uptake, and cleavage of coronavirus spike glycoproteins which activates the glycoprotein for host cell entry (PubMed:24227843, PubMed:32142651).

Created: 23 Apr 2020, 4:15 p.m. | Last Modified: 23 Apr 2020, 4:15 p.m.

Panel Version: 0.147

I don't know

PMID: 31488196 - Host susceptibility to severe influenza A virus infection, this paper reviews genes involved and identified TMPRSS2. Papers identified include:
PMID: 25904605 which reported that higher TMPRSS2 expression variant, rs2070788 GG genotype, was associated with higher susceptibility to severe illness in patients with A(H1N1)pdm09 influenza.
PMID: 24600012 showed that TMPRSS2 is the key host protease that activates IAVs in vivo through proteolytic cleavage of their HA proteins
PMID: 24522916 looked at knockout mice that do not express TMPRSS2 that are resistant to pulmonary disease with lethal outcome when infected with influenza A viruses of subtypes H7N9 and H1N1, whereas they are not protected from lethal H3N2 virus infection

This gene has also been identified in this preprint - ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy https://doi.org/10.1101/2020.03.30.20047878
Sources: Literature

Created: 20 Apr 2020, 4:26 p.m. | Last Modified: 20 Apr 2020, 4:37 p.m.

Panel Version: 0.111

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

• 31488196