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

J Exp Med. 2021 Aug 2;218(8):e20202592. doi: 10.1084/jem.20202592. Epub 2021 Jun 17.


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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Alternative Splicing / genetics
  • Child
  • Child, Preschool
  • Codon, Nonsense / genetics
  • Evolution, Molecular
  • Family
  • Female
  • Frameshift Mutation / genetics
  • Genes, Dominant*
  • Genetics, Population
  • HEK293 Cells
  • Humans
  • Infant
  • Infant, Newborn
  • Job Syndrome / genetics*
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Pedigree
  • Protein Biosynthesis
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • STAT3 Transcription Factor / genetics*


  • Codon, Nonsense
  • RNA, Messenger
  • STAT3 Transcription Factor
  • STAT3 protein, human