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Nijmegen Breakage Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder characterized by microcephaly, dysmorphic facial features, mild growth retardation, mild-to-moderate intellectual disability, premature ovarian insufficiency (hypergonadotropic hypogonadism), cellular and humoral immunodeficiency with recurrent sinopulmonary infections, radiosensitivity, and predisposition to lymphoid malignancies at an early age.
Irradiation-induced damage and the DNA damage response
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Conchita Vens, Marianne Koritzinsky, Bradly G. Wouters
The nature of the lesion dictates the presence of the initial damage-sensing protein. For example, base lesions are recognized by specific glycosylases that are designed to identify and remove the damaged base, while the loss of bases or phosphodiester bonds within DNA quickly activates poly (ADP-ribosylation)-polymerases (PARPs). DSBs are recognized by the MRN complex, consisting of three proteins: MRE11, RAD50 and NBS1. Notably, the NBS1 protein is the product of the gene that is mutated in Nijmegen breakage syndrome (NBS). As its central function in DSB recognition and repair suggests, patients with this syndrome are radiosensitive. The Ku proteins (Ku70 and 80) can also recognize and efficiently bind the ends of DSBs. Single-stranded DNA regions generated during replication or during DSBR are coated by the RPA complex. These initial DNA damage sensing events influence repair pathway choice and dictate DDR signalling through engaging different signal transduction proteins and mechanisms.
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Other ‘chromosomal breakage’ syndromes: Bloom syndrome: pre-and postnatal growth retardation, microcephaly, dolichocephaly, sun-sensitive telangiectatic erythema, patchy areas of hyper-and hypopigmentation of the skin, occasionally syndactyly or polydactyly, no further skeletal anomalies. Specific features are immunodeficiency and significant cancer predisposition, due to marked genetic instability. Caused by recessive mutations in RECQL3. Nijmegen breakage syndrome (NBS): short stature, microcephaly, neurodegeneration in infancy, cafe au lait spots, immunodeficiency, increased risk of cancer. Skeletal anomalies are not present. Caused by recessive mutations in NBS1. NBS cells can manifest chromosomal instability in PHA-stimulated lymphocytes and hypersensitivity to ionizing radiation.
Targeting the DNA damage response in pediatric malignancies
Published in Expert Review of Anticancer Therapy, 2022
Jenna M Gedminas, Theodore W Laetsch
A number of conditions are associated with inherited defects in the ATR-dependent checkpoint pathway responsible for initiating double-stranded break repair using both homologous recombination and nonhomologous end joining repair. Unrepaired double stranded DNA breaks can result in chromosome rearrangement or loss, apoptosis, or carcinogenesis [12,18]. The most common of these syndromes is ataxia telangiectasia, caused by mutations resulting in a defective ATM protein kinase. These patients are X-ray sensitive and have an increased risk for breast, ovarian, and hematologic cancers [20]. In addition, mutations in MRE11A and NBN are the cause of ataxia telangiectasia-like syndrome and Nijmegen breakage syndrome, respectively. Both disorders are associated with chromosome instability and X-ray sensitivity. Nijmegen breakage syndrome is associated with an increased risk of malignancy, while the malignancy risk in ataxia telangiectasia-like syndrome is unclear given the rarity of the disease, with only two patients reported to have developed malignancy [18,21].
Dotting the eyes: mouse strain dependency of the lens epithelium to low dose radiation-induced DNA damage
Published in International Journal of Radiation Biology, 2018
S. G. R. Barnard, J. Moquet, S. Lloyd, M. Ellender, E. A. Ainsbury, R. A. Quinlan
Studies have demonstrated a probable role of DNA damage in the lens having a role to play in cataract formation. A higher frequency of DNA single-strand breaks was reported in lens epithelial cells of cataractous patients compared to age-matched controls (Kleiman and Spector 1993). There has been discussion regarding base and nucleotide excision repair genes in cataractogenesis (Fujimichi and Hamada 2014). Polymorphisms in two genes involved in BER, OGG1 or XRCC1 result in an increased risk of senile cataract in humans. Similarly, polymorphisms in the NER associated XPD gene show the same increase in risk. In mice, mutated Xpd/Ercc2 genes result in sensitivity to ionising radiation (Kunze et al. 2015). The congenital disorder Nijmegen breakage syndrome (NBS), resulting in defective homologous recombination and chromosomal instability, reports lens opacities in a proportion of patients (Gralek et al. 2011). Heat shock transcription factor 4 (Hsf4) mutated mice develop cataract and abnormal lens fiber cell development. This protein has an important role in the gene Rad51 upregulation, crucial for DSB repair (Fujimoto et al. 2004). In humans, mutations in Hsf4 are associated with inherited cataract, the gene is considered critical to proper lens development (Bu et al. 2002). Ataxia-telangiectasia mutated protein (ATM) is recruited by DSBs to activate repair. ATM haploinsufficiency in mice leads to the development of cataract more rapidly than wild-type controls following 500 mGy exposures of X-rays (Kleiman et al. 2007). Mice defective in either MRad9 or Atm were more susceptible to cataractogenesis (Kleiman et al. 2007).
A case of premature ovarian insufficiency in Nijmegen breakage syndrome patient and review of literature. From gene mutation to clinical management
Published in Gynecological Endocrinology, 2019
Anna Szeliga, Aleksandra Zysnarska, Zuzanna Szklarska, Ewelina Truszkowska, Agnieszka Podfigurna, Adam Czyzyk, Andrea R. Genazzani, Krystyna Chrzanowska, Blazej Meczekalski
Nijmegen breakage syndrome (NBS) is an extremely rare and severe chromosomal instability disorder. Its prevalence was found to be the highest in Eastern Europe by both the International Nijmegen Breakage Syndrome Study Group and Kostyuchenko et al. [3], with the latter mentioning an occurrence rate of approximately 1:133,000 in Western Ukraine and a total of 26 patients diagnosed between 1999 and 2007 in the whole of Ukraine [4]. A 2015 retrospective analysis based upon the data obtained from the online database of the European Society for Immune Deficiencies included 149 patients diagnosed with NBS within a 9-year time frame (2004–2012), 118 of whom were registered by the documenting center in Warsaw, Poland [9].