The rare DNA ligase IV syndrome: A case report

Gerasimou, Petroula; Koumas, Laura; Miltiadous, Andri; Kyprianou, Ioannis; Chi, Jianxiang; Gavrielidou, Rafaella; Socratous, Elena; Loizou, Loizos; Papachristodoulou, Eleni; Karaoli, E.; Loizos, Anastasios; Anastasiadou, Violetta; Costeas, Paul

doi:10.1016/j.ehpc.2020.200442

Cited by 3 publications

(3 citation statements)

References 23 publications

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“…Short telomere length in white blood cells has also been found in LIG4 patients. So, the differential diagnosis of patients with the typical LIG4 syndrome (P1) includes diseases such as Fanconi anemia or dyskeratosis congenita, which can also present with dysmorphic features, bone marrow failure, and radiosensitivity ( 16 , 21 , 22 ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Wide Spectrum of Manifestations of Ligase IV Deficiency: Report of 3 Cases

et al. 2022

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DNA ligase IV deficiency is a rare autosomal recessive disorder associated with impaired DNA repair mechanisms. Most patients with DNA repair defects present with neurologic deficits, combined immunodeficiency, bone marrow failure, and/or hematologic neoplasia. We present 3 unrelated cases of ligase IV deficiency with different clinical presentations. Patient 1 presented at the age of 5 with bone marrow failure, dysmorphic features, and T and B lymphopenia. A compound heterozygous variant L19W/K635fs in the LIG4 gene was identified. Patient 2 presented at the age of 16 with recurrent infections. He had agammaglobulinemia and absent B cells. A homozygous R278H in the LIG4 gene was identified. Patient 3 was referred for vitiligo and B-cell lymphopenia (low class-switched B cells) and hypogammaglobulinemia. Homozygous R278H in LIG4 was also identified. In the last few years, the spectrum of clinical manifestations caused by ligase IV deficiency has widened, making it very difficult to establish an accurate clinical diagnosis. The use of NGS allows a proper diagnosis and provides a better prognosis and adequate family counseling.

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Section: Discussionmentioning

confidence: 99%

Case Report: Wide Spectrum of Manifestations of Ligase IV Deficiency: Report of 3 Cases

et al. 2022

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“…LIG4 and XLF/Cernunnos syndromes are rare autosomal recessive disorders with symptoms including microcephaly, severe growth delay, “bird-like” facial appearance, bony malformations, immunodeficiency and increased cellular sensitivity to IR ( Çipe et al, 2014 ; Altmann and Gennery, 2016 ; Recio et al, 2019 ; Gerasimou et al, 2020 ). These shared features are due to loss of LIG4 and NHEJ1 function in encoding key NHEJ repair elements, impairing the final rejoining.…”

Section: Microcephaly Associated With Dna Damagementioning

confidence: 99%

DNA damage and repair: underlying mechanisms leading to microcephaly

Ribeiro,

Altinisik,

Rajan

et al. 2023

Front. Cell Dev. Biol.

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DNA-damaging agents and endogenous DNA damage constantly harm genome integrity. Under genotoxic stress conditions, the DNA damage response (DDR) machinery is crucial in repairing lesions and preventing mutations in the basic structure of the DNA. Different repair pathways are implicated in the resolution of such lesions. For instance, the non-homologous DNA end joining and homologous recombination pathways are central cellular mechanisms by which eukaryotic cells maintain genome integrity. However, defects in these pathways are often associated with neurological disorders, indicating the pivotal role of DDR in normal brain development. Moreover, the brain is the most sensitive organ affected by DNA-damaging agents compared to other tissues during the prenatal period. The accumulation of lesions is believed to induce cell death, reduce proliferation and premature differentiation of neural stem and progenitor cells, and reduce brain size (microcephaly). Microcephaly is mainly caused by genetic mutations, especially genes encoding proteins involved in centrosomes and DNA repair pathways. However, it can also be induced by exposure to ionizing radiation and intrauterine infections such as the Zika virus. This review explains mammalian cortical development and the major DNA repair pathways that may lead to microcephaly when impaired. Next, we discuss the mechanisms and possible exposures leading to DNA damage and p53 hyperactivation culminating in microcephaly.

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“…In 2003, from the case of a patient suffering from a lymphoma who succumbed to its radio-chemotherapeutic treatment [ 69 , 70 ], O’Driscoll et al have defined a human syndrome associated with LIG4 mutations, characterized by high radiosensitivity, immunodeficiency, strong pancytopenia, growth retardation and dysmorphic facial features [ 54 ]. To date, in addition to this historical case, about forty cases of patients holding LIG4 mutations have been described [ 71 , 72 ].…”

Section: Diseases Of Dna Damage Repair and Signalingmentioning

confidence: 99%

Cancer and Radiosensitivity Syndromes: Is Impaired Nuclear ATM Kinase Activity the Primum Movens?

Nachef

Berthel

Ferlazzo

et al. 2022

Cancers

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There are a number of genetic syndromes associated with both high cancer risk and clinical radiosensitivity. However, the link between these two notions remains unknown. Particularly, some cancer syndromes are caused by mutations in genes involved in DNA damage signaling and repair. How are the DNA sequence errors propagated and amplified to cause cell transformation? Conversely, some cancer syndromes are caused by mutations in genes involved in cell cycle checkpoint control. How is misrepaired DNA damage produced? Lastly, certain genes, considered as tumor suppressors, are not involved in DNA damage signaling and repair or in cell cycle checkpoint control. The mechanistic model based on radiation-induced nucleoshuttling of the ATM kinase (RIANS), a major actor of the response to ionizing radiation, may help in providing a unified explanation of the link between cancer proneness and radiosensitivity. In the frame of this model, a given protein may ensure its own specific function but may also play additional biological role(s) as an ATM phosphorylation substrate in cytoplasm. It appears that the mutated proteins that cause the major cancer and radiosensitivity syndromes are all ATM phosphorylation substrates, and they generally localize in the cytoplasm when mutated. The relevance of the RIANS model is discussed by considering different categories of the cancer syndromes.

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The rare DNA ligase IV syndrome: A case report

Cited by 3 publications

References 23 publications

Case Report: Wide Spectrum of Manifestations of Ligase IV Deficiency: Report of 3 Cases

Case Report: Wide Spectrum of Manifestations of Ligase IV Deficiency: Report of 3 Cases

DNA damage and repair: underlying mechanisms leading to microcephaly

Cancer and Radiosensitivity Syndromes: Is Impaired Nuclear ATM Kinase Activity the Primum Movens?

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