Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance

Abstract

Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been recently suggested that eight out-of-frame variants operate by haploinsufficiency. We experimentally tested these 143 variants, 7 novel out-of-frame variants found in HIES patients, and other STAT3 variants from the general population. Strikingly, all 15 out-of-frame variants were DN via their encoded (1) truncated proteins, (2) neoproteins generated from a translation reinitiation codon, and (3) isoforms from alternative transcripts or a combination thereof. Moreover, 128 of the 135 in-frame variants (95%) were also DN. The patients carrying the seven non-DN STAT3 in-frame variants have not been studied for other genetic etiologies. Finally, none of the variants from the general population tested, including an out-of-frame variant, were DN. Overall, our findings show that heterozygous STAT3 variants, whether in or out of frame, underlie AD-HIES through negative dominance rather than haploinsufficiency. (© 2021 Asano et al.)Pediatr Infect Dis J. 2009 Jul;28(7):664-6. (PMID: 19483664); Blood. 2012 Apr 26;119(17):3997-4008. (PMID: 22403255); Bioinformatics. 2015 Jan 15;31(2):166-9. (PMID: 25260700); Nat Protoc. 2016 Jan;11(1):1-9. (PMID: 26633127); J Allergy Clin Immunol. 2014 May;133(5):1410-9, 1419.e1-13. (PMID: 24698316); Sci Immunol. 2018 Jun 15;3(24):. (PMID: 29907692); Immunol Rev. 2005 Feb;203:244-50. (PMID: 15661034); J Clin Immunol. 2021 Jul;41(5):864-880. (PMID: 33932191); Arthritis Rheum. 2011 Mar;63(3):830-9. (PMID: 21360512); Mol Immunol. 2008 Nov;46(1):202-6. (PMID: 18706697); J Allergy Clin Immunol. 2008 Jul;122(1):181-7. (PMID: 18602572); N Engl J Med. 2007 Oct 18;357(16):1667-8. (PMID: 17942886); J Allergy Clin Immunol. 2010 Feb;125(2):424-432.e8. (PMID: 20159255); Nature. 2007 Aug 30;448(7157):1058-62. (PMID: 17676033); J Clin Immunol. 2020 Jan;40(1):24-64. (PMID: 31953710); Blood. 2006 Dec 1;108(12):3682-90. (PMID: 16888100); Science. 2014 Sep 26;345(6204):1560-1. (PMID: 25258064); Nat Genet. 2019 May;51(5):772-776. (PMID: 30962618); J Clin Immunol. 2019 Nov;39(8):827-831. (PMID: 31468318); Sci Immunol. 2018 Jun 15;3(24):. (PMID: 29907691); Cancer Res. 2017 Nov 1;77(21):e31-e34. (PMID: 29092934); Nat Methods. 2016 Feb;13(2):109-10. (PMID: 26820543); Pediatr Allergy Immunol. 2016 Mar;27(2):177-84. (PMID: 26592211); Bioinformatics. 2010 Mar 1;26(5):589-95. (PMID: 20080505); N Engl J Med. 2009 Nov 19;361(21):2046-55. (PMID: 19776401); J Exp Med. 2009 Jun 8;206(6):1291-301. (PMID: 19487419); Mamm Genome. 2018 Aug;29(7-8):603-617. (PMID: 30094507); Genome Res. 2010 Sep;20(9):1297-303. (PMID: 20644199); J Allergy Clin Immunol. 2013 Dec;132(6):1388-96. (PMID: 24184145); Clin Nephrol. 2011 Apr;75(4):369-73. (PMID: 21426892); J Clin Immunol. 2017 Feb;37(2):166-179. (PMID: 28197791); Pediatr Allergy Immunol. 2014 Aug;25(5):503-5. (PMID: 24628715); Pediatr Int. 2004 Feb;46(1):97-100. (PMID: 15043676); Bioinformatics. 2015 Aug 15;31(16):2745-7. (PMID: 25851949); Proc Natl Acad Sci U S A. 2018 Aug 21;115(34):E8007-E8016. (PMID: 30072435); Nat Immunol. 2012 May 13;13(6):612-20. (PMID: 22581261); J Allergy Clin Immunol. 2009 Dec;124(6):1289-302.e4. (PMID: 20004785); J Res Med Sci. 2018 May 30;23:46. (PMID: 29937908); Blood. 2010 Dec 23;116(26):5895-906. (PMID: 20841510); Mol Genet Genomic Med. 2013 Nov;1(4):223-37. (PMID: 24498618); Nat Genet. 2017 Aug;49(8):1192-1201. (PMID: 28628108); J Clin Immunol. 2019 Jan;39(1):15-18. (PMID: 30617622); J Exp Med. 2017 Sep 4;214(9):2547-2562. (PMID: 28747427); Am J Hum Genet. 2011 Apr 8;88(4):440-9. (PMID: 21457909); PLoS Comput Biol. 2012;8(12):e1002806. (PMID: 23236270); Pediatrics. 1972 Jan;49(1):59-70. (PMID: 5059313); Pediatrics. 2014 Nov;134 Suppl 3:S181-2. (PMID: 25363991); Nature. 2016 Aug 17;536(7616):285-91. (PMID: 27535533); J Clin Immunol. 2013 Jul;33(5):896-902. (PMID: 23584561); Gene. 1995 Aug 19;161(2):183-7. (PMID: 7665076); J Allergy Clin Immunol. 2009 Aug;124(2):342-8, 348.e1-5. (PMID: 19577286); Proc Natl Acad Sci U S A. 2019 Aug 13;116(33):16463-16472. (PMID: 31346092); Cytokine Growth Factor Rev. 2016 Oct;31:1-15. (PMID: 27185365); Clin Immunol. 2011 Apr;139(1):75-84. (PMID: 21288777); J Family Med Prim Care. 2016 Oct-Dec;5(4):871-872. (PMID: 28349010); Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8150-5. (PMID: 15919823); J Clin Immunol. 2017 Jan;37(1):12-17. (PMID: 27844301); Lancet. 1966 May 7;1(7445):1013-5. (PMID: 4161105); PLoS One. 2014 Dec 11;9(12):e114901. (PMID: 25502423); J Allergy Clin Immunol. 2010 Jun;125(6):1389-90. (PMID: 20392475); J Clin Invest. 2019 Feb 1;129(2):583-597. (P <br />