tetano
Editor, Senior Moderator
Hum Mol Genet
. 2022 Jul 21;ddac157.
doi: 10.1093/hmg/ddac157. Online ahead of print.
ACE2 and TMPRSS2 SARS-CoV-2 infectivity genes: deep mutational scanning and characterization of missense variants
Lingxin Zhang[SUP] 1 [/SUP], Vivekananda Sarangi[SUP] 2 [/SUP], Duan Liu[SUP] 1 [/SUP], Ming-Fen Ho[SUP] 1 [/SUP], Angela R Grassi[SUP] 3 [/SUP], Lixuan Wei[SUP] 1 [/SUP], Irene Moon[SUP] 1 [/SUP], Robert A Vierkant[SUP] 2 [/SUP], Nicholas B Larson[SUP] 2 [/SUP], Konstantinos N Lazaridis[SUP] 4 5 [/SUP], Arjun P Athreya[SUP] 1 4 [/SUP], Liewei Wang[SUP] 1 4 [/SUP], Richard Weinshilboum[SUP] 1 4 [/SUP]
Affiliations
Abstract
The human ACE2 and TMPRSS2 proteins play key roles in the cellular internalization of SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic. We set out to functionally characterize the ACE2 and TMPRSS2 protein abundance for variant alleles encoding these proteins that contained non-synonymous single-nucleotide polymorphisms (nsSNPs) in their open reading frames (ORFs). Specifically, a high-throughput assay, Deep Mutational Scanning (DMS), was employed to test the functional implications of nsSNPs which are variants of uncertain significance (VUS) in these two genes. Specifically, we used a 'landing pad' system designed to quantify the protein expression for 433 nsSNPs that have been observed in the ACE2 and TMPRSS2 ORFs and found that 8 of 127 ACE2, 19 of 157 TMPRSS2 isoform 1 and 13 of 149 TMPRSS2 isoform 2 variant proteins displayed less than approximately 25% of the wild-type protein expression, while 4 ACE2 variants displayed 25% or greater increases in protein expression. As a result, we concluded that nsSNPs in genes encoding ACE2 and TMPRSS2 might potentially influence SARS-CoV-2 infectivity. These results can now be applied to DNA sequence data for patients infected with SARS-CoV-2 to determine the possible impact of patient-based DNA sequence variation on the clinical course of SARS-CoV-2 infection.
. 2022 Jul 21;ddac157.
doi: 10.1093/hmg/ddac157. Online ahead of print.
ACE2 and TMPRSS2 SARS-CoV-2 infectivity genes: deep mutational scanning and characterization of missense variants
Lingxin Zhang[SUP] 1 [/SUP], Vivekananda Sarangi[SUP] 2 [/SUP], Duan Liu[SUP] 1 [/SUP], Ming-Fen Ho[SUP] 1 [/SUP], Angela R Grassi[SUP] 3 [/SUP], Lixuan Wei[SUP] 1 [/SUP], Irene Moon[SUP] 1 [/SUP], Robert A Vierkant[SUP] 2 [/SUP], Nicholas B Larson[SUP] 2 [/SUP], Konstantinos N Lazaridis[SUP] 4 5 [/SUP], Arjun P Athreya[SUP] 1 4 [/SUP], Liewei Wang[SUP] 1 4 [/SUP], Richard Weinshilboum[SUP] 1 4 [/SUP]
Affiliations
- PMID: 35861636
- DOI: 10.1093/hmg/ddac157
Abstract
The human ACE2 and TMPRSS2 proteins play key roles in the cellular internalization of SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic. We set out to functionally characterize the ACE2 and TMPRSS2 protein abundance for variant alleles encoding these proteins that contained non-synonymous single-nucleotide polymorphisms (nsSNPs) in their open reading frames (ORFs). Specifically, a high-throughput assay, Deep Mutational Scanning (DMS), was employed to test the functional implications of nsSNPs which are variants of uncertain significance (VUS) in these two genes. Specifically, we used a 'landing pad' system designed to quantify the protein expression for 433 nsSNPs that have been observed in the ACE2 and TMPRSS2 ORFs and found that 8 of 127 ACE2, 19 of 157 TMPRSS2 isoform 1 and 13 of 149 TMPRSS2 isoform 2 variant proteins displayed less than approximately 25% of the wild-type protein expression, while 4 ACE2 variants displayed 25% or greater increases in protein expression. As a result, we concluded that nsSNPs in genes encoding ACE2 and TMPRSS2 might potentially influence SARS-CoV-2 infectivity. These results can now be applied to DNA sequence data for patients infected with SARS-CoV-2 to determine the possible impact of patient-based DNA sequence variation on the clinical course of SARS-CoV-2 infection.