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

Takaki Asano; Joëlle Khourieh; Peng Zhang; Franck Rapaport; András N Spaan; Juan Li; Wei-Te Lei; Simon J Pelham; David Hum; Maya Chrabieh; Ji Eun Han; Antoine Guérin; Joseph Mackie; Sudhir Gupta; Biman Saikia; Jamila E I Baghdadi; Ilham Fadil; Aziz Bousfiha; Tanwir Habib; Nico Marr; Luckshman Ganeshanandan; Jane Peake; Luke Droney; Andrew Williams; Fatih Celmeli; Nevin Hatipoglu; Tayfun Ozcelik; Capucine Picard; Laurent Abel; Stuart G Tangye; Stéphanie Boisson-Dupuis; Qian Zhang; Anne Puel; Vivien Béziat; Jean-Laurent Casanova; Bertrand Boisson

doi:10.1084/jem.20202592

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

Takaki Asano, Joëlle Khourieh, Peng Zhang, Franck Rapaport, András N Spaan, Juan Li, Wei-Te Lei, Simon J Pelham, David Hum, Maya Chrabieh, Ji Eun Han, Antoine Guérin, Joseph Mackie, Sudhir Gupta, Biman Saikia, Jamila E I Baghdadi, Ilham Fadil, Aziz Bousfiha, Tanwir Habib, Nico MarrLuckshman Ganeshanandan, Jane Peake, Luke Droney, Andrew Williams, Fatih Celmeli, Nevin Hatipoglu, Tayfun Ozcelik, Capucine Picard, Laurent Abel, Stuart G Tangye, Stéphanie Boisson-Dupuis, Qian Zhang, Anne Puel, Vivien Béziat, Jean-Laurent Casanova^*, Bertrand Boisson

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	e20202592
Journal	Journal of Experimental Medicine
Volume	218
Issue number	8
DOIs	https://doi.org/10.1084/jem.20202592
Publication status	Published - 2 Aug 2021
Externally published	Yes

Keywords

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
STAT3 Transcription Factor/genetics

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10.1084/jem.20202592

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Asano, T., Khourieh, J., Zhang, P., Rapaport, F., Spaan, A. N., Li, J., Lei, W.-T., Pelham, S. J., Hum, D., Chrabieh, M., Han, J. E., Guérin, A., Mackie, J., Gupta, S., Saikia, B., Baghdadi, J. E. I., Fadil, I., Bousfiha, A., Habib, T., ... Boisson, B. (2021). Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance. Journal of Experimental Medicine, 218(8), Article e20202592. https://doi.org/10.1084/jem.20202592

@article{5fbeddbde8b940c8ad3365d637804d8c,

title = "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.",

keywords = "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, STAT3 Transcription Factor/genetics",

author = "Takaki Asano and Jo{\"e}lle Khourieh and Peng Zhang and Franck Rapaport and Spaan, {Andr{\'a}s N} and Juan Li and Wei-Te Lei and Pelham, {Simon J} and David Hum and Maya Chrabieh and Han, {Ji Eun} and Antoine Gu{\'e}rin and Joseph Mackie and Sudhir Gupta and Biman Saikia and Baghdadi, {Jamila E I} and Ilham Fadil and Aziz Bousfiha and Tanwir Habib and Nico Marr and Luckshman Ganeshanandan and Jane Peake and Luke Droney and Andrew Williams and Fatih Celmeli and Nevin Hatipoglu and Tayfun Ozcelik and Capucine Picard and Laurent Abel and Tangye, {Stuart G} and St{\'e}phanie Boisson-Dupuis and Qian Zhang and Anne Puel and Vivien B{\'e}ziat and Jean-Laurent Casanova and Bertrand Boisson",

note = "Publisher Copyright: {\textcopyright} 2021 Asano et al.",

year = "2021",

month = aug,

day = "2",

doi = "10.1084/jem.20202592",

language = "English",

volume = "218",

journal = "Journal of Experimental Medicine",

issn = "0022-1007",

publisher = "Rockefeller University Press",

number = "8",

}

Asano, T, Khourieh, J, Zhang, P, Rapaport, F, Spaan, AN, Li, J, Lei, W-T, Pelham, SJ, Hum, D, Chrabieh, M, Han, JE, Guérin, A, Mackie, J, Gupta, S, Saikia, B, Baghdadi, JEI, Fadil, I, Bousfiha, A, Habib, T, Marr, N, Ganeshanandan, L, Peake, J, Droney, L, Williams, A, Celmeli, F, Hatipoglu, N, Ozcelik, T, Picard, C, Abel, L, Tangye, SG, Boisson-Dupuis, S, Zhang, Q, Puel, A, Béziat, V, Casanova, J-L & Boisson, B 2021, 'Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance', Journal of Experimental Medicine, vol. 218, no. 8, e20202592. https://doi.org/10.1084/jem.20202592

TY - JOUR

T1 - Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance

AU - Asano, Takaki

AU - Khourieh, Joëlle

AU - Zhang, Peng

AU - Rapaport, Franck

AU - Spaan, András N

AU - Li, Juan

AU - Lei, Wei-Te

AU - Pelham, Simon J

AU - Hum, David

AU - Chrabieh, Maya

AU - Han, Ji Eun

AU - Guérin, Antoine

AU - Mackie, Joseph

AU - Gupta, Sudhir

AU - Saikia, Biman

AU - Baghdadi, Jamila E I

AU - Fadil, Ilham

AU - Bousfiha, Aziz

AU - Habib, Tanwir

AU - Marr, Nico

AU - Ganeshanandan, Luckshman

AU - Peake, Jane

AU - Droney, Luke

AU - Williams, Andrew

AU - Celmeli, Fatih

AU - Hatipoglu, Nevin

AU - Ozcelik, Tayfun

AU - Picard, Capucine

AU - Abel, Laurent

AU - Tangye, Stuart G

AU - Boisson-Dupuis, Stéphanie

AU - Zhang, Qian

AU - Puel, Anne

AU - Béziat, Vivien

AU - Casanova, Jean-Laurent

AU - Boisson, Bertrand

PY - 2021/8/2

Y1 - 2021/8/2

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Alleles

KW - Alternative Splicing/genetics

KW - Child

KW - Child, Preschool

KW - Codon, Nonsense/genetics

KW - Evolution, Molecular

KW - Family

KW - Female

KW - Frameshift Mutation/genetics

KW - Genes, Dominant

KW - Genetics, Population

KW - HEK293 Cells

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Job Syndrome/genetics

KW - Male

KW - Middle Aged

KW - Mutation/genetics

KW - Pedigree

KW - Protein Biosynthesis

KW - RNA, Messenger/genetics

KW - STAT3 Transcription Factor/genetics

UR - http://www.scopus.com/inward/record.url?scp=85105376528&partnerID=8YFLogxK

U2 - 10.1084/jem.20202592

DO - 10.1084/jem.20202592

M3 - Article

C2 - 34137790

SN - 0022-1007

VL - 218

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 8

M1 - e20202592

ER -

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

Abstract

Keywords

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