Biochemically deleterious human NFKB1 variants underlie an autosomal dominant form of common variable immunodeficiency

Juan Li; Wei-Te Lei; Peng Zhang; Franck Rapaport; Yoann Seeleuthner; Bingnan Lyu; Takaki Asano; Jérémie Rosain; Boualem Hammadi; Yu Zhang; Simon J Pelham; András N Spaan; Mélanie Migaud; David Hum; Benedetta Bigio; Maya Chrabieh; Vivien Béziat; Jacinta Bustamante; Shen-Ying Zhang; Emmanuelle Jouanguy; Stephanie Boisson-Dupuis; Jamila El Baghdadi; Vishukumar Aimanianda; Katharina Thoma; Manfred Fliegauf; Bodo Grimbacher; Anne-Sophie Korganow; Carol Saunders; V Koneti Rao; Gulbu Uzel; Alexandra F Freeman; Steven M Holland; Helen C Su; Charlotte Cunningham-Rundles; Claire Fieschi; Laurent Abel; Anne Puel; Aurélie Cobat; Jean-Laurent Casanova; Qian Zhang; Bertrand Boisson

doi:10.1084/jem.20210566

Biochemically deleterious human NFKB1 variants underlie an autosomal dominant form of common variable immunodeficiency

Juan Li, Wei-Te Lei, Peng Zhang, Franck Rapaport, Yoann Seeleuthner, Bingnan Lyu, Takaki Asano, Jérémie Rosain, Boualem Hammadi, Yu Zhang, Simon J Pelham, András N Spaan, Mélanie Migaud, David Hum, Benedetta Bigio, Maya Chrabieh, Vivien Béziat, Jacinta Bustamante, Shen-Ying Zhang, Emmanuelle JouanguyStephanie Boisson-Dupuis, Jamila El Baghdadi, Vishukumar Aimanianda, Katharina Thoma, Manfred Fliegauf, Bodo Grimbacher, Anne-Sophie Korganow, Carol Saunders, V Koneti Rao, Gulbu Uzel, Alexandra F Freeman, Steven M Holland, Helen C Su, Charlotte Cunningham-Rundles, Claire Fieschi, Laurent Abel, Anne Puel, Aurélie Cobat, Jean-Laurent Casanova, Qian Zhang^*, Bertrand Boisson^*

^*Corresponding author for this work

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

Abstract

Autosomal dominant (AD) NFKB1 deficiency is thought to be the most common genetic etiology of common variable immunodeficiency (CVID). However, the causal link between NFKB1 variants and CVID has not been demonstrated experimentally and genetically, as there has been insufficient biochemical characterization and enrichment analysis. We show that the cotransfection of NFKB1-deficient HEK293T cells (lacking both p105 and its cleaved form p50) with a κB reporter, NFKB1/p105, and a homodimerization-defective RELA/p65 mutant results in p50:p65 heterodimer–dependent and p65:p65 homodimer–independent transcriptional activation. We found that 59 of the 90 variants in patients with CVID or related conditions were loss of function or hypomorphic. By contrast, 258 of 260 variants in the general population or patients with unrelated conditions were neutral. None of the deleterious variants displayed negative dominance. The enrichment in deleterious NFKB1 variants of patients with CVID was selective and highly significant (P = 2.78 × 10−¹⁵). NFKB1 variants disrupting NFKB1/p50 transcriptional activity thus underlie AD CVID by haploinsufficiency, whereas neutral variants in this assay should not be considered causal.

Original language	English
Article number	e20210566
Journal	Journal of Experimental Medicine
Volume	218
Issue number	11
DOIs	https://doi.org/10.1084/jem.20210566
Publication status	Published - 1 Nov 2021
Externally published	Yes

Keywords

Animals
COS Cells
Cell Line
Chlorocebus aethiops
Common Variable Immunodeficiency/genetics
HEK293 Cells
Haploinsufficiency/genetics
Humans
NF-kappa B p50 Subunit/genetics
NF-kappa B/genetics
Phenotype
Transcriptional Activation/genetics

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Li, J., Lei, W.-T., Zhang, P., Rapaport, F., Seeleuthner, Y., Lyu, B., Asano, T., Rosain, J., Hammadi, B., Zhang, Y., Pelham, S. J., Spaan, A. N., Migaud, M., Hum, D., Bigio, B., Chrabieh, M., Béziat, V., Bustamante, J., Zhang, S.-Y., ... Boisson, B. (2021). Biochemically deleterious human NFKB1 variants underlie an autosomal dominant form of common variable immunodeficiency. Journal of Experimental Medicine, 218(11), Article e20210566. https://doi.org/10.1084/jem.20210566

@article{8d7b637fe6644316b9dd496a3bff0ed8,

title = "Biochemically deleterious human NFKB1 variants underlie an autosomal dominant form of common variable immunodeficiency",

abstract = "Autosomal dominant (AD) NFKB1 deficiency is thought to be the most common genetic etiology of common variable immunodeficiency (CVID). However, the causal link between NFKB1 variants and CVID has not been demonstrated experimentally and genetically, as there has been insufficient biochemical characterization and enrichment analysis. We show that the cotransfection of NFKB1-deficient HEK293T cells (lacking both p105 and its cleaved form p50) with a κB reporter, NFKB1/p105, and a homodimerization-defective RELA/p65 mutant results in p50:p65 heterodimer–dependent and p65:p65 homodimer–independent transcriptional activation. We found that 59 of the 90 variants in patients with CVID or related conditions were loss of function or hypomorphic. By contrast, 258 of 260 variants in the general population or patients with unrelated conditions were neutral. None of the deleterious variants displayed negative dominance. The enrichment in deleterious NFKB1 variants of patients with CVID was selective and highly significant (P = 2.78 × 10−15). NFKB1 variants disrupting NFKB1/p50 transcriptional activity thus underlie AD CVID by haploinsufficiency, whereas neutral variants in this assay should not be considered causal.",

keywords = "Animals, COS Cells, Cell Line, Chlorocebus aethiops, Common Variable Immunodeficiency/genetics, HEK293 Cells, Haploinsufficiency/genetics, Humans, NF-kappa B p50 Subunit/genetics, NF-kappa B/genetics, Phenotype, Transcriptional Activation/genetics",

author = "Juan Li and Wei-Te Lei and Peng Zhang and Franck Rapaport and Yoann Seeleuthner and Bingnan Lyu and Takaki Asano and J{\'e}r{\'e}mie Rosain and Boualem Hammadi and Yu Zhang and Pelham, {Simon J} and Spaan, {Andr{\'a}s N} and M{\'e}lanie Migaud and David Hum and Benedetta Bigio and Maya Chrabieh and Vivien B{\'e}ziat and Jacinta Bustamante and Shen-Ying Zhang and Emmanuelle Jouanguy and Stephanie Boisson-Dupuis and {El Baghdadi}, Jamila and Vishukumar Aimanianda and Katharina Thoma and Manfred Fliegauf and Bodo Grimbacher and Anne-Sophie Korganow and Carol Saunders and Rao, {V Koneti} and Gulbu Uzel and Freeman, {Alexandra F} and Holland, {Steven M} and Su, {Helen C} and Charlotte Cunningham-Rundles and Claire Fieschi and Laurent Abel and Anne Puel and Aur{\'e}lie Cobat and Jean-Laurent Casanova and Qian Zhang and Bertrand Boisson",

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

year = "2021",

month = nov,

day = "1",

doi = "10.1084/jem.20210566",

language = "English",

volume = "218",

journal = "Journal of Experimental Medicine",

issn = "0022-1007",

publisher = "Rockefeller University Press",

number = "11",

}

Li, J, Lei, W-T, Zhang, P, Rapaport, F, Seeleuthner, Y, Lyu, B, Asano, T, Rosain, J, Hammadi, B, Zhang, Y, Pelham, SJ, Spaan, AN, Migaud, M, Hum, D, Bigio, B, Chrabieh, M, Béziat, V, Bustamante, J, Zhang, S-Y, Jouanguy, E, Boisson-Dupuis, S, El Baghdadi, J, Aimanianda, V, Thoma, K, Fliegauf, M, Grimbacher, B, Korganow, A-S, Saunders, C, Rao, VK, Uzel, G, Freeman, AF, Holland, SM, Su, HC, Cunningham-Rundles, C, Fieschi, C, Abel, L, Puel, A, Cobat, A, Casanova, J-L, Zhang, Q & Boisson, B 2021, 'Biochemically deleterious human NFKB1 variants underlie an autosomal dominant form of common variable immunodeficiency', Journal of Experimental Medicine, vol. 218, no. 11, e20210566. https://doi.org/10.1084/jem.20210566

TY - JOUR

T1 - Biochemically deleterious human NFKB1 variants underlie an autosomal dominant form of common variable immunodeficiency

AU - Li, Juan

AU - Lei, Wei-Te

AU - Zhang, Peng

AU - Rapaport, Franck

AU - Seeleuthner, Yoann

AU - Lyu, Bingnan

AU - Asano, Takaki

AU - Rosain, Jérémie

AU - Hammadi, Boualem

AU - Zhang, Yu

AU - Pelham, Simon J

AU - Spaan, András N

AU - Migaud, Mélanie

AU - Hum, David

AU - Bigio, Benedetta

AU - Chrabieh, Maya

AU - Béziat, Vivien

AU - Bustamante, Jacinta

AU - Zhang, Shen-Ying

AU - Jouanguy, Emmanuelle

AU - Boisson-Dupuis, Stephanie

AU - El Baghdadi, Jamila

AU - Aimanianda, Vishukumar

AU - Thoma, Katharina

AU - Fliegauf, Manfred

AU - Grimbacher, Bodo

AU - Korganow, Anne-Sophie

AU - Saunders, Carol

AU - Rao, V Koneti

AU - Uzel, Gulbu

AU - Freeman, Alexandra F

AU - Holland, Steven M

AU - Su, Helen C

AU - Cunningham-Rundles, Charlotte

AU - Fieschi, Claire

AU - Abel, Laurent

AU - Puel, Anne

AU - Cobat, Aurélie

AU - Casanova, Jean-Laurent

AU - Zhang, Qian

AU - Boisson, Bertrand

PY - 2021/11/1

Y1 - 2021/11/1

N2 - Autosomal dominant (AD) NFKB1 deficiency is thought to be the most common genetic etiology of common variable immunodeficiency (CVID). However, the causal link between NFKB1 variants and CVID has not been demonstrated experimentally and genetically, as there has been insufficient biochemical characterization and enrichment analysis. We show that the cotransfection of NFKB1-deficient HEK293T cells (lacking both p105 and its cleaved form p50) with a κB reporter, NFKB1/p105, and a homodimerization-defective RELA/p65 mutant results in p50:p65 heterodimer–dependent and p65:p65 homodimer–independent transcriptional activation. We found that 59 of the 90 variants in patients with CVID or related conditions were loss of function or hypomorphic. By contrast, 258 of 260 variants in the general population or patients with unrelated conditions were neutral. None of the deleterious variants displayed negative dominance. The enrichment in deleterious NFKB1 variants of patients with CVID was selective and highly significant (P = 2.78 × 10−15). NFKB1 variants disrupting NFKB1/p50 transcriptional activity thus underlie AD CVID by haploinsufficiency, whereas neutral variants in this assay should not be considered causal.

AB - Autosomal dominant (AD) NFKB1 deficiency is thought to be the most common genetic etiology of common variable immunodeficiency (CVID). However, the causal link between NFKB1 variants and CVID has not been demonstrated experimentally and genetically, as there has been insufficient biochemical characterization and enrichment analysis. We show that the cotransfection of NFKB1-deficient HEK293T cells (lacking both p105 and its cleaved form p50) with a κB reporter, NFKB1/p105, and a homodimerization-defective RELA/p65 mutant results in p50:p65 heterodimer–dependent and p65:p65 homodimer–independent transcriptional activation. We found that 59 of the 90 variants in patients with CVID or related conditions were loss of function or hypomorphic. By contrast, 258 of 260 variants in the general population or patients with unrelated conditions were neutral. None of the deleterious variants displayed negative dominance. The enrichment in deleterious NFKB1 variants of patients with CVID was selective and highly significant (P = 2.78 × 10−15). NFKB1 variants disrupting NFKB1/p50 transcriptional activity thus underlie AD CVID by haploinsufficiency, whereas neutral variants in this assay should not be considered causal.

KW - Animals

KW - COS Cells

KW - Cell Line

KW - Chlorocebus aethiops

KW - Common Variable Immunodeficiency/genetics

KW - HEK293 Cells

KW - Haploinsufficiency/genetics

KW - Humans

KW - NF-kappa B p50 Subunit/genetics

KW - NF-kappa B/genetics

KW - Phenotype

KW - Transcriptional Activation/genetics

UR - http://www.scopus.com/inward/record.url?scp=85116592517&partnerID=8YFLogxK

U2 - 10.1084/jem.20210566

DO - 10.1084/jem.20210566

M3 - Article

C2 - 34473196

SN - 0022-1007

VL - 218

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 11

M1 - e20210566

ER -

Biochemically deleterious human NFKB1 variants underlie an autosomal dominant form of common variable immunodeficiency

Abstract

Keywords

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