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.
Biochemically deleterious human NFKB1 variants underlie an autosomal dominant form of common variable immunodeficiency
Disclosures: S.J. Pelham became employed at Takeda UK Ltd. after contributing to this work. B. Grimbacher reported grants from BMBF, DFG, several pharmaceutical companies, and foundations, and personal fees from several pharmaceutical companies outside the submitted work. No other disclosures were reported.
- Award Id(s): P01AI061093
- Award Id(s): UL1TR001866
- Award Id(s): NPRP10-0206-170359
- Award Id(s): EQU201903007798
- Award Id(s): ANR-10-IAHU-01,ANR-14-CE15-0009-01,ANR-10-LABX-62-IBEID
- Award Id(s): 789645
- Award Id(s): 019.171LW.015
- Award Id(s): ALTF 84-2017
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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; Biochemically deleterious human NFKB1 variants underlie an autosomal dominant form of common variable immunodeficiency. J Exp Med 1 November 2021; 218 (11): e20210566. doi: https://doi.org/10.1084/jem.20210566
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