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

Lingxin Zhang, Vivekananda Sarangi, Duan Liu, Ming Fen Ho, Angela R. Grassi, Lixuan Wei, Irene Moon, Robert A. Vierkant, Nicholas B. Larson, Konstantinos N. Lazaridis, Arjun P. Athreya, Liewei M Wang, Richard Weinshilboum

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4183-4192
Number of pages10
JournalHuman molecular genetics
Volume31
Issue number24
DOIs
StatePublished - Dec 16 2022

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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