{"doi":"10.1093/hmg/ddac157","title":"<i>ACE2</i> and <i>TMPRSS2</i> SARS-CoV-2 infectivity genes: deep mutational scanning and characterization of missense variants","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.","journal":"Human Molecular Genetics","year":2022,"id":272976,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9557,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":336442,"name":"Vivekananda Sarangi","orcid":"0000-0002-3070-8582","position":1,"is_corresponding":false},{"id":336443,"name":"Duan Liu","orcid":"0000-0003-1065-246X","position":2,"is_corresponding":false},{"id":491976,"name":"Ming‐Fen Ho","orcid":"0000-0002-3757-3924","position":3,"is_corresponding":false},{"id":940499,"name":"Angela R Grassi","orcid":null,"position":4,"is_corresponding":false},{"id":491977,"name":"Lixuan Wei","orcid":"0000-0001-7465-7513","position":5,"is_corresponding":false},{"id":338179,"name":"Irene Moon","orcid":null,"position":6,"is_corresponding":false},{"id":311538,"name":"Robert A. Vierkant","orcid":"0000-0001-6242-5221","position":7,"is_corresponding":false},{"id":339334,"name":"Nicholas B. Larson","orcid":"0000-0002-3468-4215","position":8,"is_corresponding":false},{"id":97684,"name":"Konstantinos N. Lazaridis","orcid":"0000-0002-0437-681X","position":9,"is_corresponding":false},{"id":388473,"name":"Arjun P. Athreya","orcid":"0000-0001-9764-1768","position":10,"is_corresponding":false},{"id":228987,"name":"Liewei Wang","orcid":"0000-0003-3818-8531","position":11,"is_corresponding":false},{"id":270363,"name":"Richard M. Weinshilboum","orcid":"0000-0002-4911-7985","position":12,"is_corresponding":false},{"id":939926,"name":"Lingxin Zhang","orcid":"0000-0001-7068-7168","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T00:27:52.048702Z","pmid":"35861636","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}