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

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buir.contributor.authorÖzçelik, Tayfun
buir.contributor.orcidÖzçelik, Tayfun | 0000-0001-5937-1082
dc.citation.epage21en_US
dc.citation.issueNumber8en_US
dc.citation.spage1en_US
dc.citation.volumeNumber218en_US
dc.contributor.authorAsano, T.
dc.contributor.authorKhourieh, J.
dc.contributor.authorZhang, P.
dc.contributor.authorRapaport, F.
dc.contributor.authorSpaan, A. N.
dc.contributor.authorLi, J.
dc.contributor.authorLei, W. T.
dc.contributor.authorPelham, S. J.
dc.contributor.authorHum, D.
dc.contributor.authorChrabieh, M.
dc.contributor.authorHan, J. E.
dc.contributor.authorGuérin, A.
dc.contributor.authorMackie, J.
dc.contributor.authorGupta, S.
dc.contributor.authorSaikia, B.
dc.contributor.authorBaghdadi, J. E. I.
dc.contributor.authorFadil, I.
dc.contributor.authorBousfiha, A.
dc.contributor.authorHabib, T.
dc.contributor.authorMarr, N.
dc.contributor.authorGaneshanandan, L.
dc.contributor.authorPeake, J.
dc.contributor.authorDroney, L.
dc.contributor.authorWilliams, A.
dc.contributor.authorCelmeli, F.
dc.contributor.authorHatipoglu, N.
dc.contributor.authorÖzçelik, Tayfun
dc.contributor.authorPicard, C.
dc.date.accessioned2022-02-07T14:01:37Z
dc.date.available2022-02-07T14:01:37Z
dc.date.issued2021-06-17
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractMost 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.en_US
dc.description.provenanceSubmitted by Burcu Böke (tburcu@bilkent.edu.tr) on 2022-02-07T14:01:37Z No. of bitstreams: 1 Human_STAT3_variants_underlie_autosomal_dominant_hyper_IgE_syndrome_by_negative_dominance.pdf: 8154228 bytes, checksum: bd920ca236596ba6fac6483f4b18cbb6 (MD5)en
dc.description.provenanceMade available in DSpace on 2022-02-07T14:01:37Z (GMT). No. of bitstreams: 1 Human_STAT3_variants_underlie_autosomal_dominant_hyper_IgE_syndrome_by_negative_dominance.pdf: 8154228 bytes, checksum: bd920ca236596ba6fac6483f4b18cbb6 (MD5) Previous issue date: 2021-06-17en
dc.identifier.doi10.1084/jem.20202592en_US
dc.identifier.eissn1540-9538
dc.identifier.issn0022-1007
dc.identifier.urihttp://hdl.handle.net/11693/77122
dc.language.isoEnglishen_US
dc.publisherRockefeller University Pressen_US
dc.relation.isversionofhttps://doi.org/10.1084/jem.20202592en_US
dc.source.titleThe Journal of Experimental Medicineen_US
dc.subjectHuman disease geneticsen_US
dc.subjectImmunodeficiencyen_US
dc.subjectInfectious disease and host defenseen_US
dc.subjectInnate immunity and inflammationen_US
dc.titleHuman STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominanceen_US
dc.typeArticleen_US

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