Translational and clinical immunology
Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations

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Background

Ikaros, which is encoded by IKZF1, is a transcriptional factor that play a critical role in hematopoiesis. Somatic IKZF1 alterations are known to be involved in the pathogenesis of leukemia in human subjects. Recently, immunodeficiency caused by germline IKZF1 mutation has been described.

Objective

We sought to describe the clinical and immunologic phenotypes of Japanese patients with heterozygous IKZF1 mutations.

Methods

We performed whole-exome sequencing in patients from a dysgammaglobulinemia or autoimmune disease cohort and used a candidate gene approach in 4 patients. Functional and laboratory studies, including detailed lymphopoiesis/hematopoiesis analysis in the bone marrow, were performed.

Results

Nine patients from 6 unrelated families were identified to have heterozygous germline mutations in IKZF1. Age of onset was 0 to 20 years (mean, 7.4 years). Eight of 9 patients presented with dysgammaglobulinemia accompanied by B-cell deficiency. Four of 9 patients had autoimmune disease, including immune thrombocytopenic purpura, IgA vasculitis, and systemic lupus erythematosus. Nonautoimmune pancytopenia was observed in 1 patient. All of the mutant Ikaros protein demonstrated impaired DNA binding to the target sequence and abnormal diffuse nuclear localization. Flow cytometric analysis of bone marrow revealed reduced levels of common lymphoid progenitors and normal development of pro-B to pre-B cells.

Conclusions

Germline heterozygous IKZF1 mutations cause dysgammaglobulinemia; hematologic abnormalities, including B-cell defect; and autoimmune diseases.

Section snippets

Study approval

Informed consent was obtained from patients or their parents. The study was conducted in accordance with the Helsinki Declaration and approved by the ethics boards of the University of Toyama and Tokyo Medical and Dental University.

Genetic analysis

For whole-exome sequencing (WES), exome capture was carried out with a SureSelect Human All Exon V5 Kit (Agilent Technologies, Santa Clara, Calif), and massively parallel sequencing was performed with a HiSeq 2000 platform (Illumina, San Diego, Calif) with 100-bp

Identification of heterozygous mutations in IKZF1

Initially, we identified heterozygous IKZF1 mutations in 3 families from a dysgammaglobulinemia cohort (Table I, Fig 1, and see the Supplemental Note in this article's Online Repository at www.jacionline.org). A 7-year-old boy (A.1) had ITP and dysgammaglobulinemia with low B-cell counts at 5 years of age. Patient B.1, a 16-year-old girl, had recurrent sinopulmonary bacterial infections since 2 months of age and was treated with intravenous immunoglobulin. She also had a history of Pneumocystis

Discussion

Here we described 9 patients from 6 families with heterozygous IKZF1 mutations. We identified 5 missense mutations and 1 splice site mutation in the IKZF1. Two missense mutations (p.R162Q and p.Y210C) were previously reported,7, 9 but 4 mutations (p.C147R, p.N159S, p.R162W, and c.589+1G>A) were novel. Interestingly, the p.R162L mutation was described by Kuehn et al,9 and p.R162 might be recurrently mutated in IKZF1. All but 1 patient presented with dysgammaglobulinemia accompanied by a

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    Supported by the Research on Measures for Intractable Disease Project (to S.K.) and grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to T.M. and H.K.) and the Ministry of Health, Labour, and Welfare of Japan (to S.N.).

    Disclosure of potential conflict of interest: K. Imai has received a grant from the Ministry of Health, Labour, and Welfare (H23-012). S. Ogawa has received grants from Grant-in-Aid for Scientific Research (KAKENHI 15H05909) and the Ministry of Health, Labor and Welfare. T. Morio has received a grant from CSL-Behring. H. Kanegane has received a grant from the Japan Society for the Promotion of Science (JP26461570). The rest of the authors declare that they have no relevant conflicts of interest.

    These authors contributed equally to this work.

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