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IKAROS FAMILY ZINC FINGER 1; IKZF1

IKAROS FAMILY ZINC FINGER 1; IKZF1

Alternative titles; symbolsZINC FINGER PROTEIN, SUBFAMILY 1A, MEMBER 1; ZNFN1A1IKAROS; IK1LYF1Other entities represented in this entry:IKAROS/BCL6 FUSION GENE, I...

Alternative titles; symbols

  • ZINC FINGER PROTEIN, SUBFAMILY 1A, MEMBER 1; ZNFN1A1
  • IKAROS; IK1
  • LYF1

Other entities represented in this entry:

  • IKAROS/BCL6 FUSION GENE, INCLUDED

HGNC Approved Gene Symbol: IKZF1

Cytogenetic location: 7p12.2 Genomic coordinates (GRCh38): 7:50,303,452-50,405,100 (from NCBI)

▼ Description
The IKZF1 gene encodes a member of a family of hematopoietic zinc finger transcription factors. It is involved in gene expression via chromatin remodeling (summary by Goldman et al., 2012 and Kuehn et al., 2016).

▼ Cloning and Expression
Ikaros proteins are lymphoid-restricted zinc finger transcription factors that are considered master regulators of lymphocyte differentiation. Klug et al. (1998) noted that there are at least 8 alternatively spliced transcripts of the Ikaros gene that encode isoforms with common N-terminal and C-terminal domains. By screening a Jurkat T-cell cDNA library with a mouse Ikaros cDNA, Molnar et al. (1996) isolated human Ikaros cDNAs. The deduced human and mouse Ikaros proteins are 95% identical. RT-PCR of human thymus and peripheral blood leukocyte mRNAs detected 6 Ikaros splicing variants which were expressed at similar levels and ratios as the corresponding mouse leukocyte Ikaros transcripts. The authors found that Ikaros proteins are conserved in sequence composition and relative expression between human T cells and mouse thymocytes. Northern blot analysis demonstrated the expression of 7.5- and 4.5-kb Ikaros transcripts in human thymus, spleen, and peripheral blood leukocytes.

By PCR using primers based on a conserved nucleotide sequence of various zinc finger proteins, Nietfeld and Meyerhans (1996) cloned human bone marrow cDNAs encoding Ikaros, which they designated IK1. The deduced 519-amino acid protein is 93% identical to the mouse Ikaros isoform 1/LyF1 isoform VI and contains 4 N-terminal and 2 C-terminal zinc finger domains. The authors detected 3 human mRNA species by Northern blot analysis: a 4.4-kb transcript, which was prominent in peripheral blood leukocytes; a 6.0-kb transcript, which was strongly expressed in spleen, thymus, lymph node, and bone marrow; and a 7.0-kb transcript. They stated that the human and mouse Ikaros genes have similar overall transcription patterns.

Dijon et al. (2008) stated that the N-terminal Kruppel-like zinc finger domain of Ikaros proteins is involved in DNA binding, while the C-terminal zinc finger domain mediates homo- or heterodimerization with other Ikaros proteins. Alternative splicing of exons 3 to 6 produces Ikaros isoforms with 0 to 4 N-terminal zinc fingers, and those with at least 3 efficiently bind DNA. The DNA-binding Ikaros isoforms include IK1, IK2, IK3, and IKX, and IK4 can bind DNA on palindromic sequences. IK5, IK6, IK7, and IK8 are considered dominant-negative isoforms due to their capacity to bind other isoforms and their inefficiency in binding DNA.

▼ Gene Structure
Dijon et al. (2008) stated that the IKZF1 gene contains 7 translated exons.

▼ Mapping
Using somatic cell hybrid DNAs, Molnar et al. (1996) mapped the human Ikaros gene to 7p13-p11.1, near the EGFR gene (131550). They mapped the mouse Ikaros gene to chromosome 11 by interspecific backcross analysis.

▼ Gene Function
Harker et al. (2002) showed that Ikaros may play an important role in CD4 (186940) versus CD8 (see CD8A; 186910) lineage commitment decisions by demonstrating: (1) that it binds to regulatory elements in the endogenous CD8A locus in vivo using thymocyte chromatin immunoprecipitations; (2) that Ikaros suppresses position effect variegation of transgenes driven by CD8 regulatory elements; and (3) that mice with reduced levels of Ikaros and Aiolos (IKZF3; 606221) show an apparent increase in CD4 populations with immature phenotype, i.e., cells that fail to activate the CD8A gene. The authors proposed that Ikaros family members function as activators of the CD8A gene and that their associated activities are critical for appropriate chromatin remodeling transitions during thymocyte differentiation and lineage commitment.

Ezzat et al. (2005) demonstrated that Ikaros is expressed in the hormone-producing pituitary corticomelanotroph cells of mice, where it binds the proopiomelanocortin promoter and regulates endogenous gene expression. Ikaros-null mice had contraction of the pituitary corticomelanotroph population, reduced circulating adrenocorticotrophic hormone levels, and adrenal glucocorticoid insufficiency. Hematopoietic reconstitution failed to correct this hormonal deficit, but the phenotype of reduced body weight and diminished survival was rescued by systemic glucocorticoid-hormone administration. Ezzat et al. (2005) concluded that Ikaros plays a role in orchestrating immune-endocrine development and function.

Yap et al. (2005) identified Ikaros-binding elements in the 5-prime flanking regions of pufferfish, mouse, and human STAT4 (600558). Transactivation, electrophoretic mobility shift, and RNA interference analyses showed that Ikaros bound to the STAT4 promoter and was involved in regulation of STAT4 in human T cells.

Dijon et al. (2008) found that purified CD34 (142230)-positive human cord blood cells and adult peripheral blood cells that were cultured under erythroid conditions expressed the DNA-binding Ikaros isoforms IK1 through IK4, but not the dominant-negative isoform IK6. Immunoprecipitation analysis showed that expression of IK6 in these cells resulted in complex formation between IK6 and IK1, and IK6 decreased cell number and increased cell death. IK6 overexpression disturbed erythroid differentiation and expression of erythroid-specific genes, although it had no effect on Ikaros expression, and favored myelopoiesis by promoting expression of myeloid-specific genes.

Using quantitative proteomics, Kronke et al. (2014) found that lenalidomide, an drug effective in the treatment of multiple myeloma (254500), causes selective ubiquitination and degradation of 2 lymphoid transcription factors, IKZF1 and IKZF3, by the cereblon (CRBN; 609262)-CRL4 ubiquitin ligase complex. The CRL4 ubiquitin ligase is a complex that also contains CUL4 (see 603137) and ROC1 (603814). IKZF1 and IKZF3 are essential transcription factors in multiple myeloma. A single amino acid substitution of IKZF3 conferred resistance to lenalidomide-induced degradation and rescued lenalidomide-induced inhibition of cell growth. Similarly, Kronke et al. (2014) found that lenalidomide-induced IL2 (147680) production in T cells is due to depletion of IKZF1 and IKZF3. Kronke et al. (2014) concluded that their findings revealed a mechanism of action for a therapeutic agent: alteration of the activity of an E3 ubiquitin ligase, leading to selective degradation of specific targets.

Lu et al. (2014) independently showed that lenalidomide-bound CRBN acquires the ability to target for proteasomal degradation the B-cell transcription factors IKZF1 and IKZF3. Analysis of myeloma cell lines revealed that loss of IKZF1 and IKZF3 is both necessary and sufficient for lenalidomide's therapeutic effect, suggesting that the antitumor and teratogenic activities of thalidomide-like drugs are dissociable.

By analysis of crystal structures and biochemical screening, Fischer et al. (2014) concluded that, while the CRL4(CRBN) ligase complex is recruiting IKZF1 or IKZF3 for degradation, immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide) block endogenous substrates of the complex such as the homeobox transcription factor MEIS2 (601740) from binding. This dual activity implies that small molecules can modulate an E3 ubiquitin ligase.

Lesions in the PAX5 (167414) and IKZF1 genes, encoding B-lymphoid transcription factors, occur in over 80% of cases of pre-B-cell acute lymphoblastic leukemia (ALL; see 613065). By combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, Chan et al. (2017) identified a novel B-lymphoid program for transcriptional repression of glucose and energy supply. The metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, resulting in constitutive activation of the energy-stress sensor AMPK (see 602739). Dominant-negative mutants of PAX5 and IKZF1 however, relieved this glucose and energy restriction. In a transgenic pre-B ALL mouse model, the heterozygous deletion of Pax5 increased glucose uptake and ATP levels by more than 25-fold. Reconstitution of PAX5 and IKZF1 in samples from patients with pre-B ALL restored a nonpermissive state and induced energy crisis and cell death. A CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets identified the products of NR3C1 (138040), encoding the glucocorticoid receptor, TXNIP (605051), encoding a glucose feedback sensor, and CNR2 (605051), encoding a cannabinoid receptor, as central effectors of B-lymphoid restriction of glucose and energy supply. Notably, transport-independent lipophilic methyl-conjugates of pyruvate and tricarboxylic acid cycle metabolites bypassed the gatekeeper function of PAX5 and IKZF1 and readily enabled leukemic transformation. Conversely, pharmacologic TXNIP and CNR2 agonists and a small-molecule AMPK inhibitor strongly synergized with glucocorticoids, identifying TXNIP, CNR2, and AMPK as potential therapeutic targets. Furthermore, these results provided a mechanistic explanation for the empirical finding that glucocorticoids are effective in the treatment of B-lymphoid but not myeloid malignancies. Thus, B-lymphoid transcription factors function as metabolic gatekeepers by limiting the amount of cellular ATP to levels that are insufficient for malignant transformation.

Schjerven et al. (2017) established a model of inducible Ikaros expression in patient-derived IKZF1-mutant BCR-ABL1-positive pre-B ALL cells that naturally express the dominant-negative IK6 isoform. Using integrated genomewide chromatin and expression analysis after Ikaros restoration in these cells, the authors identified Ikaros-regulated target genes (e.g., CTNND1; 601045) and pathways that downregulated genes from progenitor programs. Zinc finger-4 (ZF4) of Ikaros was required for developmental downregulation of Kit (164920) in mouse progenitor B cells, and aberrant Kit expression correlated with loss of tumor suppressor function in mouse cells with a deletion of Ikaros ZF4. IKAROS regulated developmental stage-specific expression of CD34 and CD43 (SPN; 182160) in human pre-B ALL. Deregulated expression of CD43 and CD34 in IKZF1-mutant pre-B ALL conferred leukemic growth advantage. Schjerven et al. (2017) concluded that Ikaros tumor suppressor function is deregulated in the context of IKZF1 mutations, leading to increased leukemogenesis.

▼ Molecular Genetics
Common Variable Immunodeficiency 13

In an infant with a severe form of common variable immunodeficiency-13 (CVID13; 616873), Goldman et al. (2012) identified a de novo heterozygous missense mutation in the IKZF1 gene (Y210C; 603023.0001). The mutation was found by targeted sequencing of the IKZF1 gene because of the phenotypic similarities of the patient compared to that of the Ikzf1-null mouse (see ANIMAL MODEL). In vitro functional expression studies showed that the mutant protein had decreased DNA-binding affinity to pericentromeric heterochromatin compared to wildtype, consistent with a loss of function. (In the article by Goldman et al. (2012), the protein change is given as tyrosine210 for cysteine as well as cysteine210 for tyrosine.)

In affected members of 4 unrelated families with CVID13, Kuehn et al. (2016) identified 4 different heterozygous missense mutations in the IKZF1 gene (603023.0002-603023.0005). Affected individuals in a fifth family with the disorder had a heterozygous intragenic deletion affecting the IKZF1 gene (603023.0006), and affected individuals in a sixth family had a heterozygous larger deletion of chromosome 7 involving 11 genes, including IKZF1. In vitro functional expression studies of the missense mutations showed that all the mutant proteins had abnormal and diffuse localization of mutant IKZF1 within the nucleus, indicating that they do not properly localize to pericentromeric heterochromatin, suggesting functional impairment. Although the missense mutant proteins were able to dimerize with the wildtype protein, there was no evidence for a dominant-negative effect, suggesting haploinsufficiency as the mechanism of pathogenesis.

Role in Acute Lymphoblastic Leukemia

Ikaros is required for normal lymphocyte development. Germline mutant mice that express only non-DNA-binding dominant-negative 'leukemogenic' Ikaros isoforms lacking critical N-terminal zinc fingers develop an aggressive form of lymphoblastic leukemia 3 to 6 months after birth (see 'Animal Model' below). These facts prompted Sun et al. (1999) to seek molecular abnormalities involving the Ikaros gene in acute lymphoblastic leukemia (ALL2; 613067) in infants. In leukemic cells from 12 ALL infants less than 1 year of age, Sun et al. (1999) found high-level expression of dominant-negative isoforms of Ikaros with abnormal subcellular compartmentalization patterns. PCR cloning and nucleotide sequencing were used to identify the specific Ikaros isoforms and detect Ikaros gene mutations in these cells. Leukemic cells from 7 of 7 infants with ALL, including 5 of 5 MLL-AF4-positive (159557) infants, expressed dominant-negative Ikaros isoforms IK4, IK7, and IK8 that lack critical N-terminal zinc fingers. In 6 of 7 patients, Sun et al. (1999) detected an in-frame deletion of 10 amino acids (KSSMPQKFLG) upstream of the transcription-activation domain adjacent to the C-terminal zinc fingers of IK2, IK4, IK7, and IK8. In contrast, only wildtype IK1 and IK2 isoforms with normal nuclear localization were found in normal infant bone marrow cells and infant thymocytes. These results implicated the expression of dominant-negative Ikaros isoforms and the disruption of normal Ikaros function in the leukemogenesis of ALL in infants.

Nakase et al. (2000) found overexpression of the dominant-negative IK6 isoform in 14 of 41 B-cell patients with adult B-cell ALL. None of the other dominant-negative isoforms of the Ikaros gene were detected by RT-PCR analysis. Southern blot analysis with PstI digestion revealed that those patients with the dominant-negative IK6 isoform might have small mutations in the Ikaros locus. The results suggested that Ikaros plays a key role in human B-cell malignancies through the dominant-negative isoform IK6.

Using RT-PCR to detect Ikaros isoforms with the 30-base deletion in exon 6, Payne et al. (2001) showed that transcripts for IK1 and IK1 with the deletion were present in normal cord blood and bone marrow, as well as in 3 ALL cell lines. In addition, they identified an isoform, IKX, that was identical to IK3 except that it included exon 6; IKX was generated from a novel exon combination with and without the 30-base deletion. Payne et al. (2001) detected multiple DNA-binding and nonbinding isoforms with a 60-base insertion linked to leukemia expressed at the RNA level in normal hemopoietic cells. Immunoblot analysis indicated that the predominant isoform in normal cells is IKX, while the predominant form in leukemic cells is IK1.

In a genomewide analysis of leukemic cells from 242 pediatric ALL patients using high resolution, single-nucleotide polymorphism (SNP) arrays and genomic DNA sequencing, Mullighan et al. (2007) identified mutations in genes encoding principal regulators of B-lymphocyte development and differentiation in 40% of B-progenitor ALL cases. Deletions were detected in IKZF1, IKZF3 (606221),TCF3 (147141), EBF1 (164343), and LEF1 (153245). The PAX5 (167414) gene was the most frequent target of somatic mutation, being altered in 31.7% of cases.

The Philadelphia chromosome, a chromosomal abnormality that encodes BCR-ABL1 (see 151410, 189980), is the defining lesion of chronic myelogenous leukemia (CML) and a subset of acute lymphoblastic leukemia (ALL). To define oncogenic lesions that cooperate with BCR-ABL1 to induce ALL, Mullighan et al. (2008) performed a genomewide analysis of diagnostic leukemia samples from 304 individuals with ALL, including 43 BCR-ABL1 B-progenitor ALLs and 23 CML cases. IKZF1, encoding the transcription factor Ikaros, was deleted in 83.7% of BCR-ABL1 ALL, but not in chronic phase CML. Deletion of IKZF1 was also identified as an acquired lesion at the time of transformation of CML to ALL (lymphoid blast crisis). The IKZF1 deletions resulted in haploinsufficiency, expression of a dominant-negative Ikaros isoform, or the complete loss of Ikaros expression. Sequencing of IKZF1 deletion breakpoints suggested that aberrant RAG-mediated recombination (see 179615) is responsible for the deletions. Mullighan et al. (2008) concluded that genetic lesions resulting in the loss of Ikaros function are an important event in the development of BCR-ABL1 ALL.

Mullighan et al. (2009) identified deletions involving the IKZF1 gene in leukemic cells of 63 (28.6%) of 221 children with B-cell acute lymphoblastic leukemia. Cells from 20 patients had a deletion of coding exons 3 through 6, resulting in the expression of a dominant-negative form of IKZF1. IKZF1 deletions were associated with an increased risk of relapse and adverse effects in the original cohort and in an independent cohort of 258 patients (p values ranging from less than 0.001 to 0.004).

▼ Cytogenetics
The BCL6 gene (109565), isolated from the breakpoints of 3q27-associated chromosomal translocations, is implicated in diffuse large B-cell lymphomas (DLBL). Hosokawa et al. (2000) described the molecular characterization of novel t(3;7)(q27;p12) translocations in 2 patients with DLBL. Molecular genetic analysis of the breakpoint area involving BCL6 revealed the presence of the Ikaros gene. As a molecular consequence of the translocation, the 5-prime regulatory region of BCL6 was replaced by the putative 5-prime regulatory region of the Ikaros gene, probably leading to deregulated expression of the BCL6 gene throughout B-cell differentiation. RT-PCR and FISH analyses of a patient sample established that the translocation resulted in fusion of the Ikaros and BCL6 genes. The clinical features of the 2 patients with DLBL and t(3;7)(q27;p12) translocations were reported by Ichinohasama et al. (1998).

▼ Animal Model
Mice homozygous for a germline mutation in the Ikaros DNA-binding domain lack not only T and B lymphocytes and natural killer cells, but also their earliest defined progenitors (Georgopoulos et al., 1994). In contrast, the erythroid and myeloid lineages are intact in these mutant mice. Klug et al. (1998) showed that the DNA-binding isoforms of mouse Ikaros are localized in the nucleus of the most primitive hematopoietic stem cell subset. They found that Ikaros localizes to heterochromatin in Abelson-transformed pre-B lymphocytes. Changes in the RNA splicing pattern of Ikaros occurred at 2 stages of lymphoid differentiation.

O'Neill et al. (1999, 2000) described the structure of a chromatin remodeling complex associated with Ikaros that is present only in adult hematopoietic cells. This complex binds to Ikaros-like DNA-binding sites, including a long polypyrimidine-rich sequence upstream of the human delta-globin gene (142000), and was thus called PYR complex. Deletion of this sequence in a human beta locus-containing cosmid (carrying sequences from the human gamma-A gene, 142200, through the adult beta-globin gene, 141900) in transgenic mice resulted in delayed switching from gamma-globin to beta-globin. Lopez et al. (2002) showed that homozygous Ikaros-null mice lacked the PYR complex, demonstrating a requirement for Ikaros in the formation of the complex on DNA. Heterozygous Ikaros-null mice had about half as much PYR complex, indicating a dosage effect for both Ikaros and PYR complex. They also showed that Ikaros-null mice had multiple hematopoietic cell defects, including anemia and megakaryocytic abnormalities, in addition to lymphoid and stem cell defects. The null mice also had a delay in murine embryonic-to-adult beta-globin switching and a delay in human gamma-to-beta switching, consistent with the suggested role for PYR complex in this process. Lastly, cDNA array analyses indicated that several hematopoietic cell-specific genes in all blood lineages were either up- or downregulated in 14-day embryos from Ikaros-null mice compared with wildtype mice. These results indicated that Ikaros and PYR complex function together in vivo at many adult hematopoietic cell-specific genes and at intergenic sites, affecting their expression and leading to pleiotropic hematopoietic defects.

Plasmacytoid dendritic cells are specialized dendritic cells that produce high levels of type I interferon (see IFNA1; 147660) upon viral infection. Allman et al. (2006) showed that mice expressing low levels of Ikaros lacked peripheral plasmacytoid dendritic cells but not other dendritic cell subsets. Loss of plasmacytoid dendritic cells was associated with inability to produce type I interferon after challenge with Tlr7 (300365) or Tlr9 (605474) ligands or murine cytomegalovirus. Conventional dendritic cells were present in normal numbers and exhibited normal responses to in vivo challenge with murine cytomegalovirus or inactivated toxoplasma antigen.

Schjerven et al. (2017) observed increased growth using pre-B cells from an Ikzf1 mutant mouse strain with targeted deletion of ZF4 (ZF4 -/-) in a model of BCR-ABL1 compared with pre-B cells from wildtype mice or ZF1 -/- mice. ZF4 -/- BCR-Abl1 cells initiated an aggressive leukemia when transplanted into an immunocompetent host. Loss of Ikaros tumor suppressor function corresponded to a less-mature cell surface phenotype without blocking successful IgH V(D)J recombination. Expression profiling revealed Ikaros target genes and deregulated signaling pathways, including Wnt/Ctnnb (see 116806), in ZF4 -/- leukemic cells. Schjerven et al. (2017) concluded that Ikaros mediates tumor suppressor function by enforcing proper developmental stage-specific expression of multiple genes through chromatin compaction at its target genes.

▼ ALLELIC VARIANTS ( 6 Selected Examples):

.0001 IMMUNODEFICIENCY, COMMON VARIABLE, 13
IKZF1, TYR210CYS
In an infant with common variable immunodeficiency-13 (CVID13; 616873), Goldman et al. (2012) identified a de novo heterozygous c.629A-G transition in exon 5 of the IKZF1 gene, resulting in a tyr210-to-cys (Y210C) substitution in the beta-turn of the fourth DNA-binding zinc finger. The mutation was found by targeted sequencing of the IKZF1 gene because of the phenotypic similarities of the patient compared to that of the Ikzf1-null mouse; it was not found in 12 control individuals. In vitro functional expression studies showed that the mutant protein had decreased DNA-binding affinity to pericentromeric heterochromatin compared to wildtype, consistent with a loss of function. Patient cells showed abnormal and diffuse localization of mutant IKZF1 within the nucleus, indicating that it does not properly localize to pericentromeric heterochromatin, suggesting functional impairment.

In contrast, Kuehn et al. (2016) observed normal pericentromeric localization of the Y210C protein in transfected cells. These authors also found that the Y210C mutation resulted in decreased, but not absent, DNA binding.

.0002 IMMUNODEFICIENCY, COMMON VARIABLE, 13
IKZF1, ARG162LEU
In a mother and son with common variable immunodeficiency-13 (CVID13; 616873), Kuehn et al. (2016) identified a heterozygous c.485G-T transversion (c.485G-T, NM_006060) in the IKZF1 gene, resulting in an arg162-to-leu (R162L) substitution at a highly conserved residue in zinc finger 2 at a DNA contact site. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the 1000 Genomes Project or ExAC databases. A different mutation at the same codon was identified in another family with the same disorder (R162Q; 603023.0003).

.0003 IMMUNODEFICIENCY, COMMON VARIABLE, 13
IKZF1, ARG162GLN
In 7 affected members of a family with common variable immunodeficiency-13 (CVID13; 616873), Kuehn et al. (2016) identified a heterozygous c.485G-A transition (c.485G-A, NM_006060) in the IKZF1 gene, resulting in an arg162-to-gln (R162Q) substitution at a highly conserved residue in zinc finger 2 at a DNA contact site. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the 1000 Genomes Project or ExAC databases. A different mutation at the same codon was identified in another family with the same disorder (R162L; 603023.0002).

.0004 IMMUNODEFICIENCY, COMMON VARIABLE, 13
IKZF1, HIS167ARG
In a mother and her 2 daughters with common variable immunodeficiency-13 (CVID13; 616873), Kuehn et al. (2016) identified a heterozygous c.500A-G transition (c.500A-G, NM_006060) in the IKZF1 gene, resulting in a his167-to-arg (H167R) substitution at a highly conserved residue in zinc finger 2. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the 1000 Genomes Project or ExAC databases.

.0005 IMMUNODEFICIENCY, COMMON VARIABLE, 13
IKZF1, ARG184GLN
In a mother and daughter with common variable immunodeficiency-13 (CVID13; 616873), Kuehn et al. (2016) identified a heterozygous c.551G-A transition (c.551G-A, NM_006060) in the IKZF1 gene, resulting in an arg184-to-gln (R184Q) substitution at a highly conserved residue in zinc finger 3 at a DNA contact site. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the 1000 Genomes Project or ExAC databases.

.0006 IMMUNODEFICIENCY, COMMON VARIABLE, 13
IKZF1, 16.8-KB DEL
In a father and son with common variable immunodeficiency-13 (CVID13; 616873), Kuehn et al. (2016) identified a heterozygous 16.8-kb intragenic deletion (chr7.50,435,843_50,452,713del, NM_006060) in the IKZF1 gene, resulting in an in-frame deletion of exons 4 and 5. The deletion was predicted to result in the loss of zinc fingers 1, 2, and 3. The deletion, which was found by whole-exome sequencing and array-based GCH, was confirmed by Sanger sequencing and segregated with the disorder in the family.

Tags: 7p12.2