Three Types of Immunodeficiency, Centromeric Instability, and Facial Anomalies (ICF) Syndrome Identified by Whole-Exome Sequencing in Saudi Hypogammaglobulinemia Patients: Clinical, Molecular, and Cytogenetic Features

Alghamdi, Hamza Ali; Tashkandi, Suha; Al-Idrissi, Eman; Aledielah, Rawan D.; AlSaidi, Khelad A.; Alharbi, Enas S.; Habazi, Murad K.

doi:10.1007/s10875-018-0569-9

Cited by 14 publications

(7 citation statements)

References 9 publications

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“…However, we do not observe significant increases in cell death/apoptosis or reduced growth in Lsh-deficient lymphocytes (without BMT) in short-term in vitro cultures, and a report using primary lymphocytes derived from an ICF4 patient found normal proliferation in response to mitogens and is consistent with our results ( 30 ). Furthermore, ICF4 patients have normal peripheral B and T cell numbers ( 29 , 30 ), consistent with our observation in Lsh-deficient mice that are not undergoing bone marrow reconstitution. The reported differences in cellular survival may be due to the use of an aneuploid transformed cell line ( 55 , 56 ) versus primary cells (this study and Kubota et al ( 30 )), culture conditions, the use of IL-4 which promotes B cell survival ( 57 , 58 ), the duration of cell culture since prolonged culture can perturb DNA methylation patterns in lymphoid cell lines including satellites ( 59 ), or the age of the subject from which ICF cells are derived (we used young mice).…”

Section: Discussionsupporting

confidence: 90%

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Lsh/HELLS is required for B lymphocyte development and immunoglobulin class switch recombination

Ren

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Mutation of HELLS (Helicase, Lymphoid-Specific)/Lsh in human DNA causes a severe immunodeficiency syndrome, but the nature of the defect remains unknown. We assessed here the role of Lsh in hematopoiesis using conditional Lsh knockout mice with expression of Mx1 or Vav Cre-recombinase. Bone marrow transplantation studies revealed that Lsh depletion in hematopoietic stem cells severely reduced B cell numbers and impaired B cell development in a hematopoietic cell-autonomous manner. Lsh-deficient mice without bone marrow transplantation exhibited lower Ig levels in vivo compared to controls despite normal peripheral B cell numbers. Purified B lymphocytes proliferated normally but produced less immunoglobulins in response to in vitro stimulation, indicating a reduced capacity to undergo class switch recombination (CSR). Analysis of germline transcripts, examination of double-stranded breaks using biotin-labeling DNA break assay, and End-seq analysis indicated that the initiation of the recombination process was unscathed. In contrast, digestion–circularization PCR analysis and high-throughput sequencing analyses of CSR junctions and a chromosomal break repair assay indicated an impaired ability of the canonical end-joining pathway in Lsh-deficient B cells. Our data suggest a hematopoietic cell-intrinsic role of Lsh in B cell development and in CSR providing a potential target for immunodeficiency therapy.

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Section: Discussionsupporting

confidence: 90%

“…ICF4 patients display reduced Ig levels in the presence of normal lymphocyte numbers and no apparent in vitro proliferation defect in response to mitogens ( 29 , 30 ). We noted that Lsh KO mice that had not received BMT displayed reduced serum levels of IgG1, IgG2a, and IgG3 compared to Ctrls ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Lsh/HELLS is required for B lymphocyte development and immunoglobulin class switch recombination

Ren

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Nonsense mutations in zinc-finger and BTB domain-containing 24 ( ZBTB24 ) are found in approximately 30% of ICF patients, referred to as ICF2 [62]. Twelve ICF cases with mutations in cell division cycle associated 7 ( CDCA7 ) or in helicase, lymphoid specific ( HELLS ) have been reported [63,64], and are referred to as ICF3 and ICF4, respectively. A few patients remain who showed molecular and phenotypic features characteristic of ICF syndrome but do not have mutations in the four known genes, and were referred to as ICFX [51].…”

Section: The Genetics Of Icf Syndromementioning

confidence: 99%

DNA methylation in disease: Immunodeficiency, Centromeric instability, Facial anomalies syndrome

Vukić

Daxinger

2019

Essays in Biochemistry

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DNA methylation is an epigenetic modification essential for normal mammalian development. Initially associated with gene silencing, more diverse roles for DNA methylation in the regulation of gene expression patterns are increasingly being recognized. Some of these insights come from studying the function of genes that are mutated in human diseases characterized by abnormal DNA methylation landscapes. The first disorder to be associated with congenital defects in DNA methylation was Immunodeficiency, Centromeric instability, Facial anomalies syndrome (ICF). The hallmark of this syndrome is hypomethylation of pericentromeric satellite repeats, with mutations in four genes: DNMT3B, ZBTB24, CDCA7 and HELLS, being linked to the disease. Here, we discuss recent progress in understanding the molecular interactions between these genes and consider current evidence for how aberrant DNA methylation may contribute to the abnormal phenotype present in ICF syndrome patients.

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“…IgRT, as well as prophylactic antimicrobials, have also been reported in other DNA repair defects, such as ICF, ligase 1 deficiency, RNF168 deficiency, GINS1 deficiency, and POLE2 deficiency [ 47 , 51 , 65 , 70 , 72 , 75 , 77 , 78 ].…”

Section: Prevention Of Infectionsmentioning

confidence: 99%

Infections in DNA Repair Defects

Demirdağ

Gupta

2023

Pathogens

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DNA repair defects are heterogenous conditions characterized by a wide spectrum of clinical phenotypes. The common presentations of DNA repair defects include increased risk of cancer, accelerated aging, and defects in the development of various organs and systems. The immune system can be affected in a subset of these disorders leading to susceptibility to infections and autoimmunity. Infections in DNA repair defects may occur due to primary defects in T, B, or NK cells and other factors such as anatomic defects, neurologic disorders, or during chemotherapy. Consequently, the characteristics of the infections may vary from mild upper respiratory tract infections to severe, opportunistic, and even fatal infections with bacteria, viruses, or fungi. Here, infections in 15 rare and sporadic DNA repair defects that are associated with immunodeficiencies are discussed. Because of the rarity of some of these conditions, limited information is available regarding infectious complications.

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Three Types of Immunodeficiency, Centromeric Instability, and Facial Anomalies (ICF) Syndrome Identified by Whole-Exome Sequencing in Saudi Hypogammaglobulinemia Patients: Clinical, Molecular, and Cytogenetic Features

Cited by 14 publications

References 9 publications

Lsh/HELLS is required for B lymphocyte development and immunoglobulin class switch recombination

Lsh/HELLS is required for B lymphocyte development and immunoglobulin class switch recombination

DNA methylation in disease: Immunodeficiency, Centromeric instability, Facial anomalies syndrome

Infections in DNA Repair Defects

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