{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Rael VE"],"funding":["Lupus Research Institute","Children's Mercy Research Institute","Howard Hughes Medical Institute","NIAID NIH HHS","Office of the NIH","National Institutes of Health","Office of Strategic Coordination","Chan-Zuckerburg Biohub Physician Scientist Fellowship Program","Centers for Disease Control and Prevention","NHGRI NIH HHS","NINDS NIH HHS","NIAMS NIH HHS","Children’s Mercy Research Institute","NCIRD CDC HHS","NIH HHS","CDC HHS","National Science Foundation"],"pagination":["e20232005"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11116816"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["221(8)"],"pubmed_abstract":["Nucleic acid-sensing Toll-like receptors (TLR) 3, 7/8, and 9 are key innate immune sensors whose activities must be tightly regulated to prevent systemic autoimmune or autoinflammatory disease or virus-associated immunopathology. Here, we report a systematic scanning-alanine mutagenesis screen of all cytosolic and luminal residues of the TLR chaperone protein UNC93B1, which identified both negative and positive regulatory regions affecting TLR3, TLR7, and TLR9 responses. We subsequently identified two families harboring heterozygous coding mutations in UNC93B1, UNC93B1+/T93I and UNC93B1+/R336C, both in key negative regulatory regions identified in our screen. These patients presented with cutaneous tumid lupus and juvenile idiopathic arthritis plus neuroinflammatory disease, respectively. "],"journal":["The Journal of experimental medicine"],"pubmed_title":["Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans."],"pmcid":["PMC11116816"],"funding_grant_id":["U01 HG007703","T32 AI100829","U01 HG010218","5T32AR079068-03","T32 AR079068","U01IP001050","U01 IP001050","U01 NS134356","U01 NS134355","U01HG010218","R01AI072429","1752814","R01 AI072429"],"pubmed_authors":["Dasari S","Cole FS","Undiagnosed Diseases Network","Emrick LT","Wener M","Novacic D","Malicdan MCV","Taylor H","Worley K","Sutton S","Becker ML","Allenspach EJ","Cunningham M","Yano JA","Butte MJ","Jobanputra V","Walker M","Slayden LC","Stoler JM","Jean-Marie O","Bonner D","Gropman A","Loo SK","Seto E","Farrow EG","Coakley TR","Barton GM","Pallais JC","Fieg EL","Papp JC","Bellen HJ","Acosta MT","Posey JE","Lanza IR","Silverman EK","Miller D","Dayal JG","Jarvik GP","Vogel TP","Adams DR","Krakow D","Byers P","Martin MG","Huizar JP","Shelkowitz E","Bale J","Fisher PG","Fogel BL","Maghiro A","Mahoney R","Renteria G","Sinsheimer JS","Lanpher BC","Izumi K","Scott DA","McCray AT","Phillips JA","Whitlock J","Petcharet L","Sweetser DA","Zuo W","Alvey J","Tran AA","Macnamara EF","Cobban LA","Raper A","Davis J","Turcotte EA","Tarakad A","Marth G","Cogan JD","Wang LK","Bivona S","Tabor HK","Sharma P","Wenger T","Pusey Swerdzewski BN","Bejerano G","Bonner DE","Jarvik J","Craigen WJ","Might M","Wangler MF","Pak S","Zuchner S","Bayrak-Toydemir P","Hisama FM","Martin BA","Hayes N","Longo N","Ketkar S","Rosenfeld JA","Mao R","Saxton RA","Liu P","Sullivan K","Mamounas LA","Wambach J","Alvarez RL","Lalani SR","Dorrani N","Parker NH","Blue E","Rael VE","Orengo JP","Thorson W","Wheeler MT","Hing A","Horike-Pyne M","Weiss MA","Martinez-Agosto JA","Bennett J","Kilich G","Bamshad M","Corona R","Zhang Z","Tekin M","Eng CM","D'Souza P","Liu B","Hom J","Kravets E","Hanchard N","Nelson SF","Halley MC","Smith KS","Sheppeard S","Sybert V","Delgado M","Introne W","Krasnewich DM","Bohnsack J","Urv TK","Majer O","Tifft CJ","Wan J","Baldridge D","Lewis RA","Holm IA","Solomon B","Solnica-Krezel L","Clark GD","Rodan LH","Afzali B","Byrd WE","Kohane IS","Nieves-Rodriguez S","Pastinen T","Beck A","Moretti P","Potocki L","Crouse AB","Glass I","Mikati M","Wegner D","Doss AL","Hutchison S","Rives L","Coggins M","Andrews A","Kiley D","Kohler JN","Shashi V","Behrens E","Tan ALM","Botto L","Ashley EA","Bacino CA","Chanprasert S","Eckstein DJ","Barbouth D","Briere LC","Quinlan A","Ruzhnikov M","Beggs AH","Marwaha S","Nakano-Okuno M","Huang Y","Thiffault I","Hamid R","Fu J","Reuter CM","Dai H","Spillmann RC","Goddard PC","Sisco K","Vanderver A","Balasubramanyam A","Burrage LC","Morimoto M","Shin J","Brown G","Schoch K","Otten C","Marom R","Ungar RA","Manolio TA","Toro C","Pace L","Lee BH","Cassini T","Chao HT","Huang A","Oglesbee D","Velinder M","McConkie-Rosell A","Stergachis A","Morava E","Maduro VV","Yamamoto S","Jenkins JL","Viskochil D","Carey J","Sampson JB","Bademci G","Falk M","High F","Bernstein JA","Berry GT","Bican A","Burke EA","Kobren SN","LeBlanc K","Lam C","Rossignol F","Walley NM","Robertson AK","Hassey K","Ward PA","Earl D","McGee E","MacRae CA","Hubshman MW","Kaitryn E","Rosenthal E","Chinn I","Doherty D","Mirzaa G","Allworth A","Terry JM","Maas RL","Colley HA","Gahl WA","Loscalzo J","Mulvihill JJ","Schedl T","Jayadev S","Rao DA","Stevens AM","Dipple K","Wolfe LA","Korrick S","Raskind W","Dell'Angelica EC","Godfrey RA","Tan QK","Wong SC","Westerfield M","Douine ED","Sabaii M","Wahl CE"],"additional_accession":[]},"is_claimable":false,"name":"Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans.","description":"Nucleic acid-sensing Toll-like receptors (TLR) 3, 7/8, and 9 are key innate immune sensors whose activities must be tightly regulated to prevent systemic autoimmune or autoinflammatory disease or virus-associated immunopathology. Here, we report a systematic scanning-alanine mutagenesis screen of all cytosolic and luminal residues of the TLR chaperone protein UNC93B1, which identified both negative and positive regulatory regions affecting TLR3, TLR7, and TLR9 responses. We subsequently identified two families harboring heterozygous coding mutations in UNC93B1, UNC93B1+/T93I and UNC93B1+/R336C, both in key negative regulatory regions identified in our screen. These patients presented with cutaneous tumid lupus and juvenile idiopathic arthritis plus neuroinflammatory disease, respectively. ","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Aug","modification":"2026-07-15T07:52:15.334Z","creation":"2026-07-01T03:07:52.974Z"},"accession":"S-EPMC11116816","cross_references":{"pubmed":["38780621"],"doi":["10.1084/jem.20232005"]}}