Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency
David Boutboul, … , Sylvain Latour, Sergio D. Rosenzweig
David Boutboul, … , Sylvain Latour, Sergio D. Rosenzweig
Published June 11, 2018
Citation Information: J Clin Invest. 2018;128(7):3071-3087. https://doi.org/10.1172/JCI98164.
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Research Article Genetics Immunology

Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency

Abstract

Ikaros/IKZF1 is an essential transcription factor expressed throughout hematopoiesis. IKZF1 is implicated in lymphocyte and myeloid differentiation and negative regulation of cell proliferation. In humans, somatic mutations in IKZF1 have been linked to the development of B cell acute lymphoblastic leukemia (ALL) in children and adults. Recently, heterozygous germline IKZF1 mutations have been identified in patients with a B cell immune deficiency mimicking common variable immunodeficiency. These mutations demonstrated incomplete penetrance and led to haploinsufficiency. Herein, we report 7 unrelated patients with a novel early-onset combined immunodeficiency associated with de novo germline IKZF1 heterozygous mutations affecting amino acid N159 located in the DNA-binding domain of IKZF1. Different bacterial and viral infections were diagnosed, but Pneumocystis jirovecii pneumonia was reported in all patients. One patient developed a T cell ALL. This immunodeficiency was characterized by innate and adaptive immune defects, including low numbers of B cells, neutrophils, eosinophils, and myeloid dendritic cells, as well as T cell and monocyte dysfunctions. Notably, most T cells exhibited a naive phenotype and were unable to evolve into effector memory cells. Functional studies indicated these mutations act as dominant negative. This defect expands the clinical spectrum of human IKZF1-associated diseases from somatic to germline, from haploinsufficient to dominant negative.

Authors

David Boutboul, Hye Sun Kuehn, Zoé Van de Wyngaert, Julie E. Niemela, Isabelle Callebaut, Jennifer Stoddard, Christelle Lenoir, Vincent Barlogis, Catherine Farnarier, Frédéric Vely, Nao Yoshida, Seiji Kojima, Hirokazu Kanegane, Akihiro Hoshino, Fabian Hauck, Ludovic Lhermitte, Vahid Asnafi, Philip Roehrs, Shaoying Chen, James W. Verbsky, Katherine R. Calvo, Ammar Husami, Kejian Zhang, Joseph Roberts, David Amrol, John Sleaseman, Amy P. Hsu, Steven M. Holland, Rebecca Marsh, Alain Fischer, Thomas A. Fleisher, Capucine Picard, Sylvain Latour, Sergio D. Rosenzweig

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Figure 1

Pedigree analysis in patients with IKZF1N159S/T mutations.

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Pedigree analysis in patients with IKZF1N159S/T mutations. (A) Pedigrees...
(A) Pedigrees of 7 kindreds with IKZF1N159S/T mutations (families A–G). Affected individuals are shown in black. Diagonal lines indicate deceased individuals. WT, wild-type allele; Mut, mutant allele. “E?” indicates unknown genotype. (B) Schematic representation of the IKZF1 coding region, from exon 1 to 8, and corresponding domains, shown in dark gray: the DNA-binding domain containing 4 ZFs and the dimerization domain containing 2 ZFs. Sites of mutations are shown on top with predicted combined annotation dependent depletion (CADD) scores. (C) Alignment of the ZF1-4 DNA-binding domains of IKZF1. Two cysteines and 2 histidines (C2H2) in each finger are responsible for Zn2+ coordination (bottom connecting lines), except for ZF4, in which the last histidine is replaced by a cysteine (strictly conserved in the Ikaros-like family). Amino acids at positions –1, –4, –7, and –8 relative to the first histidine (i.e., 0) are known to be involved in DNA binding (19). Mutated amino acids are colored in pink (this study) or orange (previous studies). The ZF predicted secondary structures (deduced from the model of 3D structure shown in Supplemental Figure 8) are shown below the alignment. (D) Alignment of ZF domains of IKZF1 family members including IKZF1/IKAROS, IKZF2/HELIOS, IKZF3/AIOLOS, and IKZF4/EOS. Sequences of species from the Chordata phylum including marine Urochordata (Ciona and Oikopleura) and primitive fish such as hagfish are aligned. Red stars indicate residues found to be mutated in patients. All these residues are highly conserved through species.