Clinical variability and expression of the NBN c.657del5 allele in Nijmegen Breakage Syndrome

Lins, Stephan; Kim, Ryong; Krüger, Lars; Chrzanowska, Krystyna; Seemanová, E; Digweed, Martin

doi:10.1016/j.gene.2009.07.013

Cited by 14 publications

(8 citation statements)

References 26 publications

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“…Patient cells showed approximately 1.5 times the level of ROS after DNA damage in comparison to control cells whilst in null mutant mouse cells the levels were more than two fold increased. We have previously described individual variations in the level of p70-nibrin expression [16] which are due to differences in its proteasomal degradation [49]. Low levels of p70-nibrin correlate with cancer incidence and it can be speculated that a contributing factor may be higher oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

DNA Damage in Nijmegen Breakage Syndrome Cells Leads to PARP Hyperactivation and Increased Oxidative Stress

et al. 2012

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Nijmegen Breakage Syndrome (NBS), an autosomal recessive genetic instability syndrome, is caused by hypomorphic mutation of the NBN gene, which codes for the protein nibrin. Nibrin is an integral member of the MRE11/RAD50/NBN (MRN) complex essential for processing DNA double-strand breaks. Cardinal features of NBS are immunodeficiency and an extremely high incidence of hematological malignancies. Recent studies in conditional null mutant mice have indicated disturbances in redox homeostasis due to impaired DSB processing. Clearly this could contribute to DNA damage, chromosomal instability, and cancer occurrence. Here we show, in the complete absence of nibrin in null mutant mouse cells, high levels of reactive oxygen species several hours after exposure to a mutagen. We show further that NBS patient cells, which unlike mouse null mutant cells have a truncated nibrin protein, also have high levels of reactive oxygen after DNA damage and that this increased oxidative stress is caused by depletion of NAD+ due to hyperactivation of the strand-break sensor, Poly(ADP-ribose) polymerase. Both hyperactivation of Poly(ADP-ribose) polymerase and increased ROS levels were reversed by use of a specific Poly(ADP-ribose) polymerase inhibitor. The extremely high incidence of malignancy among NBS patients is the result of the combination of a primary DSB repair deficiency with secondary oxidative DNA damage.

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Section: Discussionmentioning

confidence: 99%

DNA Damage in Nijmegen Breakage Syndrome Cells Leads to PARP Hyperactivation and Increased Oxidative Stress

et al. 2012

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“…14,15 Although genotyping common founder mutations in NBS is a useful diagnostic approach, the detection of elevated ␣-fetoprotein serum levels or truncations of the ATM protein is more practicable in AT. [16][17][18] The therapeutic perspective for AT and NBS patients has made considerable progress during recent years, providing evidence for successful stem cell transplantation in NBS and slowdown of neurodegeneration in AT using antioxidants and poly(ADPribose) polymerase inhibitors. 19,20 Novel treatment strategies also might arise from the use of translational read-through compounds to correct the ATM gene function, whereas the substitution of immunoglobulin preparations is commonplace practice to treat the humoral immunodeficiency in NBS and to improve the clinical outcome.…”

Section: Diagnostic Procedures For Routine Prospective Guthrie Card Amentioning

confidence: 99%

Neonatal screening for severe primary immunodeficiency diseases using high-throughput triplex real-time PCR

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Döbeln

Fasth

et al. 2012

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“…A gene dosage effect has been recorded for NBS patients too, with cancer occurrence lower in a subgroup of patients with above average p70-nibrin levels [117]. The individual variation in p70-nibrin levels is thought to reflect differences in its proteolytic turnover rather than differences in expression level [118]. …”

Section: Aetiopathogenesismentioning

confidence: 99%

Nijmegen breakage syndrome (NBS)

Chrzanowska

Gregorek

Dembowska‐Bagińska

et al. 2012

Orphanet J Rare Dis

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Nijmegen breakage syndrome (NBS) is a rare autosomal recessive syndrome of chromosomal instability mainly characterized by microcephaly at birth, combined immunodeficiency and predisposition to malignancies. Due to a founder mutation in the underlying NBN gene (c.657_661del5) the disease is encountered most frequently among Slavic populations. The principal clinical manifestations of the syndrome are: microcephaly, present at birth and progressive with age, dysmorphic facial features, mild growth retardation, mild-to-moderate intellectual disability, and, in females, hypergonadotropic hypogonadism. Combined cellular and humoral immunodeficiency with recurrent sinopulmonary infections, a strong predisposition to develop malignancies (predominantly of lymphoid origin) and radiosensitivity are other integral manifestations of the syndrome. The NBN gene codes for nibrin which, as part of a DNA repair complex, plays a critical nuclear role wherever double-stranded DNA ends occur, either physiologically or as a result of mutagenic exposure. Laboratory findings include: (1) spontaneous chromosomal breakage in peripheral T lymphocytes with rearrangements preferentially involving chromosomes 7 and 14, (2) sensitivity to ionizing radiation or radiomimetics as demonstrated in vitro by cytogenetic methods or by colony survival assay, (3) radioresistant DNA synthesis, (4) biallelic hypomorphic mutations in the NBN gene, and (5) absence of full-length nibrin protein. Microcephaly and immunodeficiency are common to DNA ligase IV deficiency (LIG4 syndrome) and severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation due to NHEJ1 deficiency (NHEJ1 syndrome). In fact, NBS was most commonly confused with Fanconi anaemia and LIG4 syndrome. Genetic counselling should inform parents of an affected child of the 25% risk for further children to be affected. Prenatal molecular genetic diagnosis is possible if disease-causing mutations in both alleles of the NBN gene are known. No specific therapy is available for NBS, however, hematopoietic stem cell transplantation may be one option for some patients. Prognosis is generally poor due to the extremely high rate of malignancies.Zespół Nijmegen (Nijmegen breakage syndrome; NBS) jest rzadkim schorzeniem z wrodzoną niestabilnością chromosomową dziedziczącym się w sposób autosomalny recesywny, charakteryzującym się przede wszystkim wrodzonym małogłowiem, złożonymi niedoborami odporności i predyspozycją do rozwoju nowotworów.Choroba występuje najczęściej w populacjach słowiańskich, w których uwarunkowana jest mutacją założycielską w genie NBN (c.657_661del5). Do najważniejszych objawów zespołu zalicza się: małogłowie obecne od urodzenia i postępujące z wiekiem, charakterystyczne cechy dysmorfii twarzy, opóźnienie wzrastania, niepełnosprawność intelektualną w stopniu lekkim do umiarkowanego oraz hipogonadyzm hipogonadotropowy u dziewcząt. Na obraz choroby składają się także: niedobór odporności komórkowej i humoralnej, który jest przyczyną naw...

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Clinical variability and expression of the NBN c.657del5 allele in Nijmegen Breakage Syndrome

Cited by 14 publications

References 26 publications

DNA Damage in Nijmegen Breakage Syndrome Cells Leads to PARP Hyperactivation and Increased Oxidative Stress

DNA Damage in Nijmegen Breakage Syndrome Cells Leads to PARP Hyperactivation and Increased Oxidative Stress

Neonatal screening for severe primary immunodeficiency diseases using high-throughput triplex real-time PCR

Nijmegen breakage syndrome (NBS)

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