Germline
            <i>IKZF1</i>
            mutations and their impact on immunity: IKAROS-associated diseases and pathophysiology

Nunes-Santos, Cristiane J.; Rosenzweig, Sergio D.

doi:10.1080/1744666x.2021.1901582

Cited by 22 publications

(26 citation statements)

References 60 publications

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“…IKZF2 is annotated with a high pLI (probability of loss of function intolerance) score of 0.99 (gnomAD v2.1.1) and compared to the pLI of other genes causing inborn errors of immunity (IEIs) in haploinsufficient state, ranks 4 th out of 13 (supplemental Figure 1A), indicating strong susceptibility to haploinsufficiency 14 . Interestingly, the patient's asymptomatic father carries the same variant, indicating incomplete penetrance 15 , a feature that has also been reported in other IEIs including germline heterozygous IKZF1 mutations 16 .…”

Section: Clinical Phenotype and Identification Of Ikzf2 Variantsupporting

confidence: 66%

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Identification of germline monoallelic mutations in IKZF2 in patients with immune dysregulation

et al. 2022

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Helios, encoded by IKZF2, is a member of the Ikaros family of transcription factors with pivotal roles in T-follicular helper, NK- and T-regulatory cell physiology. Somatic IKZF2 mutations are frequently found in lymphoid malignancies. Although germline mutations in IKZF1 and IKZF3, encoding Ikaros and Aiolos, have recently been identified in patients with phenotypically similar immunodeficiency syndromes, the effect of germline mutations in IKZF2 on human hematopoiesis and immunity remains enigmatic. We identified germline IKZF2 mutations (one nonsense (p.R291X)- and 4 distinct missense variants) in six patients with systemic lupus erythematosus, immune thrombocytopenia or EBV-associated hemophagocytic lymphohistiocytosis. Patients exhibited hypogammaglobulinemia, decreased number of T-follicular helper and NK-cells. Single-cell RNA sequencing of PBMCs from the patient carrying the R291X variant revealed upregulation of pro-inflammatory genes associated with T-cell receptor activation and T-cell exhaustion. Functional assays revealed the inability of HeliosR291X to homodimerize and bind target DNA as dimers. Moreover, proteomic analysis by proximity-dependent Biotin Identification revealed aberrant interaction of 3/5 Helios mutants with core components of the NuRD complex conveying HELIOS-mediated epigenetic and transcriptional dysregulation.

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Section: Clinical Phenotype and Identification Of Ikzf2 Variantsupporting

confidence: 66%

“… 14 Interestingly, the patient’s asymptomatic father carried the same variant, indicating incomplete penetrance, 15 a feature that has also been reported in other IEIs, including germline heterozygous IKZF1 mutations. 16 …”

Section: Resultsmentioning

confidence: 99%

Identification of germline monoallelic mutations in IKZF2 in patients with immune dysregulation

et al. 2022

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“…In recent years, our group and others have reported several different germline heterozygous mutations causing various immune defects in human patients [reviewed in (54)(55)(56)] leading to different forms of IKAROS-associated diseases. Since 2012, over 30 different variants in IKZF1 have been identified across more than 100 individuals to cause various manifestations of immunological defects.…”

Section: Ikzf1 In Human Diseasementioning

confidence: 99%

“…The majority of these mutations lie within the functional regions of IKZF1, clustering mostly around ZF2 and ZF3 (part of the DNA binding domain) or ZF5 and ZF6 (the dimerization domain). Few mutations have been found outside of these functional domains and only one mutation has been reported in ZF1 ( 56 , 57 ). Both large gene deletions and single missense mutations have been identified to cause immunological defects in individuals, the location of which can underly the pathomechanism of disease.…”

Section: Ikzf1 In Human Diseasementioning

confidence: 99%

“…To date, more than 16 different HI mutations have been reported in patients with common variable immunodeficiency (CVID) phenotypes. More than 65 individuals have shown to carry the HI mutations and about one third of them are asymptomatic mutation carriers ( 54 , 56 ). The presence of asymptomatic cases in HI IKZF1 mutations compared with DN mutations, suggests either incomplete penetrance or delayed onset of disease.…”

Section: Ikzf1 In Human Diseasementioning

confidence: 99%

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Ikaros-Associated Diseases: From Mice to Humans and Back Again

2021

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The normal expression of Ikaros (IKZF1) is important for the proper functioning of both the human and murine immune systems. Whilst our understanding of IKZF1 in the immune system has been greatly enhanced by the study of mice carrying mutations in Ikzf1, analyses of human patients carrying germline IKZF1 mutations have been instrumental in understanding its biological role within the human immune system and its effect on human disease. A myriad of different mutations in IKZF1 have been identified, spanning across the entire gene causing differential clinical outcomes in patients including immunodeficiency, immune dysregulation, and cancer. The majority of mutations in humans leading to IKAROS-associated diseases are single amino acid heterozygous substitutions that affect the overall function of the protein. The majority of mutations studied in mice however, affect the expression of the protein rather than its function. Murine studies would suggest that the complete absence of IKZF1 expression leads to severe and sometimes catastrophic outcomes, yet these extreme phenotypes are not commonly observed in patients carrying IKZF1 heterozygous mutations. It is unknown whether this discrepancy is simply due to differences in zygosity, the role and regulation of IKZF1 in the murine and human immune systems, or simply due to a lack of similar controls across both groups. This review will focus its analysis on the current literature surrounding what is known about germline IKZF1 defects in both the human and the murine immune systems, and whether existing mice models are indeed accurate tools to study the effects of IKZF1-associated diseases.

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Risk assessment and genetic counseling for hematologic malignancies—Practice resource of the National Society of Genetic Counselors

Stewart,

Helber,

Bannon

et al. 2024

Journal of Genetic Counseling

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Hematologic malignancies (HMs) are a heterogeneous group of cancers impacting individuals of all ages that have been increasingly recognized in association with various germline predisposition syndromes. Given the myriad of malignancy subtypes, expanding differential diagnoses, and unique sample selection requirements, evaluation for hereditary predisposition to HM presents both challenges as well as exciting opportunities in the ever‐evolving field of genetic counseling. This practice resource has been developed as a foundational resource for genetic counseling approaches to hereditary HMs and aims to empower genetic counselors who encounter individuals and families with HMs in their practice.

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Germline IKZF1 mutations and their impact on immunity: IKAROS-associated diseases and pathophysiology

Cited by 22 publications

References 60 publications

Identification of germline monoallelic mutations in IKZF2 in patients with immune dysregulation

Identification of germline monoallelic mutations in IKZF2 in patients with immune dysregulation

Ikaros-Associated Diseases: From Mice to Humans and Back Again

Risk assessment and genetic counseling for hematologic malignancies—Practice resource of the National Society of Genetic Counselors

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