Epigenetic Alterations in Inborn Errors of Immunity

Romanò, Roberta; Cillo, Francesca; Moracas, Cristina; Pignata, Laura; Nannola, Chiara; Toriello, Elisabetta; Rosa, A. De; Cirillo, Emilia; Coppola, Emma; Giardino, Giuliana; Brunetti‐Pierri, Nicola; Riccio, Andrea; Pignata, Claudio

doi:10.3390/jcm11051261

Cited by 18 publications

(10 citation statements)

References 88 publications

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“…DNA methylation is the pivotal molecular hallmark that exerts pleiotropic effects leading to a wide range of impairments, which result in a multisystemic syndrome. Disruptions in the epigenome are increasingly being recognized as a common pathogenic mechanism underlying rare Inborn Errors of Immunity (30). DNMT3B is the only gene among those involved in the ICF syndrome pathogenesis that is clearly associated with DNA methylation homeostasis (31).…”

Section: Discussionmentioning

confidence: 99%

A novel iPSC-based model of ICF syndrome subtype 2 recapitulates the molecular phenotype of ZBTB24 deficiency

Lullo,

Cecere,

Batti

et al. 2024

Preprint

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Immunodeficiency, Centromeric instability and Facial anomalies (ICF) syndrome is a rare genetic disorder characterized by variable immunodeficiency. More than half of the affected individuals show mild to severe intellectual disability at early onset. This disorder is genetically heterogeneous and ZBTB24 is the causative gene of the subtype 2, accounting for about 30% of the ICF cases. ZBTB24 is a multifaceted transcription factor belonging to the Zinc-finger and BTB domain-containing protein family, which are key regulators of developmental processes. Aberrant DNA methylation is the main molecular hallmark of ICF syndrome. The functional link between ZBTB24 deficiency and DNA methylation errors is still elusive. Here, we generated a novel ICF2 disease model by deriving induced pluripotent stem cells (iPSCs) from peripheral CD34+-blood cells of a patient homozygous for the p.Cys408Gly mutation, the most frequent missense mutation in ICF2 patients and which is associated with a broad clinical spectrum. The mutation affects a conserved cysteine of the ZBTB24 zinc-finger domain, perturbing its function as transcriptional activator. ICF2-iPSCs recapitulate the methylation defects associated with ZBTB24 deficiency, including centromeric hypomethylation. We validated that the mutated ZBTB24 protein loses its ability to directly activate expression of CDCA7 and other target genes in the patient-derived iPSCs. Upon hematopoietic differentiation, ICF2-iPSCs showed decreased vitality and a lower percentage of CD34+/CD43+/CD45+ progenitors. Overall, the ICF2-iPSC model is highly relevant to explore the role of ZBTB24 in DNA methylation homeostasis and provides a tool to investigate the early molecular events linking ZBTB24 deficiency to the ICF2 clinical phenotype.

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Section: Discussionmentioning

confidence: 99%

A novel iPSC-based model of ICF syndrome subtype 2 recapitulates the molecular phenotype of ZBTB24 deficiency

Lullo,

Cecere,

Batti

et al. 2024

Preprint

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“…These include epigenetic mechanisms, which are better explained in the following sections. In particular, epigenetic regulation is extremely variable as a consequence of TBX1 hemizygosity, which creates a random epigenetic marking that varies from cell to cell [ 84 , 89 ]. In some, the deletion may unmask recessive mutations in genes located in the intact 22q11.2 region, leading to atypical and more severe presentations of 22q11.2DS [ 21 ].…”

Section: Genetic Features Of 22q112dsmentioning

confidence: 99%

Understanding the Variability of 22q11.2 Deletion Syndrome: The Role of Epigenetic Factors

Cillo,

Coppola,

Habetswallner

et al. 2024

Genes

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Initially described as a triad of immunodeficiency, congenital heart defects and hypoparathyroidism, 22q11.2 deletion syndrome (22q11.2DS) now encompasses a great amount of abnormalities involving different systems. Approximately 85% of patients share a 3 Mb 22q11.2 region of hemizygous deletion in which 46 protein-coding genes are included. However, the hemizygosity of the genes of this region cannot fully explain the clinical phenotype and the phenotypic variability observed among patients. Additional mutations in genes located outside the deleted region, leading to “dual diagnosis”, have been described in 1% of patients. In some cases, the hemizygosity of the 22q11.2 region unmasks autosomal recessive conditions due to additional mutations on the non-deleted allele. Some of the deleted genes play a crucial role in gene expression regulation pathways, involving the whole genome. Typical miRNA expression patterns have been identified in 22q11.2DS, due to an alteration in miRNA biogenesis, affecting the expression of several target genes. Also, a methylation epi-signature in CpG islands differentiating patients from controls has been defined. Herein, we summarize the evidence on the genetic and epigenetic mechanisms implicated in the pathogenesis of the clinical manifestations of 22q11.2 DS. The review of the literature confirms the hypothesis that the 22q11.2DS phenotype results from a network of interactions between deleted protein-coding genes and altered epigenetic regulation.

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“…Fine-tuning of epigenetic processes in the immune system is required for punctual gene transcription during differentiation of the hematopoietic stem cell (HSC) and lymphoid and myeloid lineage commitment. Genetic defects in some IEI genes potentially can affect the DNA methylation signatures and histone modification patterns and contribute to the pathogenesis of clinical manifestations, including malignancy phenotype [26]. Moreover, this mechanism has been proposed as the main cause of some unknown IEI disorders without monogenic mutation but with high susceptibility to cancers including common variable immunodeficiency or IgA deficiency [27][28][29].…”

Section: Nonmutational Epigenetic Reprogrammingmentioning

confidence: 99%

Updates of cancer hallmarks in patients with inborn errors of immunity

Wang

Abolhassani

2022

Current Opinion in Allergy &Amp; Clinical Immunology

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Purpose of reviewThe development of cancer in patients with genetically determined inborn errors of immunity (IEI) is much higher than in the general population. The hallmarks of cancer are a conceptualization tool that can refine the complexities of cancer development and pathophysiology. Each genetic defect may impose a different pathological tumor predisposition, which needs to be identified and linked with known hallmarks of cancer.Recent findingsFour new hallmarks of cancer have been suggested, recently, including unlocking phenotypic plasticity, senescent cells, nonmutational epigenetic reprogramming, and polymorphic microbiomes. Moreover, more than 50 new IEI genes have been discovered during the last 2 years from which 15 monogenic defects perturb tumor immune surveillance in patients.SummaryThis review provides a more comprehensive and updated overview of all 14 cancer hallmarks in IEI patients and covers aspects of cancer predisposition in novel genes in the ever-increasing field of IEI.

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Epigenetic Alterations in Inborn Errors of Immunity

Cited by 18 publications

References 88 publications

A novel iPSC-based model of ICF syndrome subtype 2 recapitulates the molecular phenotype of ZBTB24 deficiency

A novel iPSC-based model of ICF syndrome subtype 2 recapitulates the molecular phenotype of ZBTB24 deficiency

Understanding the Variability of 22q11.2 Deletion Syndrome: The Role of Epigenetic Factors

Updates of cancer hallmarks in patients with inborn errors of immunity

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