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ACE2 and TMPRSS2 SARS-CoV-2 infectivity genes: deep mutational scanning and characterization of missense variants

The human angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) proteins play key roles in the cellular internalization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus responsible for the coronavirus disease of 2019 (COVID-19) pandemic....

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Autores principales: Zhang, Lingxin, Sarangi, Vivekananda, Liu, Duan, Ho, Ming-Fen, Grassi, Angela R, Wei, Lixuan, Moon, Irene, Vierkant, Robert A, Larson, Nicholas B, Lazaridis, Konstantinos N, Athreya, Arjun P, Wang, Liewei, Weinshilboum, Richard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9759330/
https://www.ncbi.nlm.nih.gov/pubmed/35861636
http://dx.doi.org/10.1093/hmg/ddac157
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author Zhang, Lingxin
Sarangi, Vivekananda
Liu, Duan
Ho, Ming-Fen
Grassi, Angela R
Wei, Lixuan
Moon, Irene
Vierkant, Robert A
Larson, Nicholas B
Lazaridis, Konstantinos N
Athreya, Arjun P
Wang, Liewei
Weinshilboum, Richard
author_facet Zhang, Lingxin
Sarangi, Vivekananda
Liu, Duan
Ho, Ming-Fen
Grassi, Angela R
Wei, Lixuan
Moon, Irene
Vierkant, Robert A
Larson, Nicholas B
Lazaridis, Konstantinos N
Athreya, Arjun P
Wang, Liewei
Weinshilboum, Richard
author_sort Zhang, Lingxin
collection PubMed
description The human angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) proteins play key roles in the cellular internalization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus responsible for the coronavirus disease of 2019 (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 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 ~25% of the wild-type protein expression, whereas 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.
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spelling pubmed-97593302022-12-19 ACE2 and TMPRSS2 SARS-CoV-2 infectivity genes: deep mutational scanning and characterization of missense variants Zhang, Lingxin Sarangi, Vivekananda Liu, Duan Ho, Ming-Fen Grassi, Angela R Wei, Lixuan Moon, Irene Vierkant, Robert A Larson, Nicholas B Lazaridis, Konstantinos N Athreya, Arjun P Wang, Liewei Weinshilboum, Richard Hum Mol Genet Original Article The human angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) proteins play key roles in the cellular internalization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus responsible for the coronavirus disease of 2019 (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 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 ~25% of the wild-type protein expression, whereas 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. Oxford University Press 2022-07-21 /pmc/articles/PMC9759330/ /pubmed/35861636 http://dx.doi.org/10.1093/hmg/ddac157 Text en © The Author(s) 2022. Published by Oxford University Press. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Zhang, Lingxin
Sarangi, Vivekananda
Liu, Duan
Ho, Ming-Fen
Grassi, Angela R
Wei, Lixuan
Moon, Irene
Vierkant, Robert A
Larson, Nicholas B
Lazaridis, Konstantinos N
Athreya, Arjun P
Wang, Liewei
Weinshilboum, Richard
ACE2 and TMPRSS2 SARS-CoV-2 infectivity genes: deep mutational scanning and characterization of missense variants
title ACE2 and TMPRSS2 SARS-CoV-2 infectivity genes: deep mutational scanning and characterization of missense variants
title_full ACE2 and TMPRSS2 SARS-CoV-2 infectivity genes: deep mutational scanning and characterization of missense variants
title_fullStr ACE2 and TMPRSS2 SARS-CoV-2 infectivity genes: deep mutational scanning and characterization of missense variants
title_full_unstemmed ACE2 and TMPRSS2 SARS-CoV-2 infectivity genes: deep mutational scanning and characterization of missense variants
title_short ACE2 and TMPRSS2 SARS-CoV-2 infectivity genes: deep mutational scanning and characterization of missense variants
title_sort ace2 and tmprss2 sars-cov-2 infectivity genes: deep mutational scanning and characterization of missense variants
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9759330/
https://www.ncbi.nlm.nih.gov/pubmed/35861636
http://dx.doi.org/10.1093/hmg/ddac157
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