title: The Common R71H-G230A-R293Q Human TMEM173 Is a Null Allele.
abstract: TMEM173 encodes MPYS/STING and is an innate immune sensor for cyclic dinucleotides (CDNs) playing a critical role in infection, inflammation, and cancer. The R71H-G230A-R293Q (HAQ) of TMEM173 is the second most common human TMEM173 allele. In this study, using data from the 1000 Genomes Project we found that homozygous HAQ individuals account for ∼16.1% of East Asians and ∼2.8% of Europeans whereas Africans have no homozygous HAQ individuals. Using B cells from homozygous HAQ carriers, we found, surprisingly, that HAQ/HAQ carriers express extremely low MPYS protein and have a decreased TMEM173 transcript. Consequently, the HAQ/HAQ B cells do not respond to CDNs. We subsequently generated an HAQ knock-in mouse expressing a mouse equivalent of the HAQ allele (mHAQ). The mHAQ mouse has decreased MPYS protein in B cells, T cells, Ly6Chimonocytes, bone marrow-derived dendritic cells, and lung tissue. The mHAQ mouse also does not respond to CDNs in vitro and in vivo. Lastly, Pneumovax 23, with an efficacy that depends on TMEM173, is less effective in mHAQ mice than in wild type mice. We conclude that HAQ is a null TMEM173 allele. Our findings have a significant impact on research related to MPYS-mediated human diseases and medicine.
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL 32610.
authors.forename: Seema
authors.identifier: 0000-0001-7303-5288
authors.initials: S
authors.lastname: Patel
authors.affiliation: Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208.
authors.forename: Steven M
authors.identifier: 0000-0002-9391-4084
authors.initials: SM
authors.lastname: Blaauboer
authors.affiliation: Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208.
authors.forename: Heidi R
authors.initials: HR
authors.lastname: Tucker
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL 32610.|Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208.
authors.forename: Samira
authors.initials: S
authors.lastname: Mansouri
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité University Medicine Berlin, 13353 Berlin, Germany; and.
authors.forename: Juan Sebastian
authors.identifier: 0000-0002-4661-7802
authors.initials: JS
authors.lastname: Ruiz-Moreno
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité University Medicine Berlin, 13353 Berlin, Germany; and.
authors.forename: Lutz
authors.initials: L
authors.lastname: Hamann
authors.affiliation: Institute of Microbiology and Hygiene, Charité University Medicine Berlin, 10117 Berlin, Germany.
authors.forename: Ralf R
authors.initials: RR
authors.lastname: Schumann
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité University Medicine Berlin, 13353 Berlin, Germany; and.
authors.forename: Bastian
authors.initials: B
authors.lastname: Opitz
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL 32610; lei.jin@medicine.ufl.edu.|Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208.
authors.forename: Lei
authors.identifier: 0000-0001-6836-1142
authors.initials: L
authors.lastname: Jin
mesh_terms: D000483:Alleles; D000818:Animals; D055879:Gene Knock-In Techniques; D005838:Genotype; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009712:Nucleotides, Cyclic / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099197:STING Protein
chemical_list: D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; C532857:STING1 protein, human; D000099197:STING Protein