Nijmegen breakage syndrome (NBS) with neurological abnormalities and without chromosomal instability

Seemanová, E; Sperling, Karl; Neitzel, Heidemarie; Varon, Raymonda; Hadač, Jan; Butova, Olga; Schröck, Evelin; Seeman, Pavel; Digweed, Martin

doi:10.1136/jmg.2005.035287

Cited by 45 publications

(63 citation statements)

References 25 publications

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“…Overall, these results support a dominant-negative function of the Arg215Trp mutation with respect to the 657del5 ''founder mutation'' (27,35), which might explain also the phenotypic differences between the twin NBS brothers compound heterozygous Arg215Trp/657del5 and the patients with NBS homozygous for the 657del5 mutation (35). However, the reason because both the heterozygous carriers of the Arg215Trp NBN mutation and the twin brothers compound heterozygous Arg215Trp/657del5 do not show chromosomal instability remains still unclear (35,56).…”

Section: Discussionsupporting

confidence: 52%

“…The patients with NBS characterized by the compound heterozygosity for the 657del5 and 643C[T (Arg215Trp) mutations within the NBN gene display a more severe phenotype than patients with NBS homozygous for the 657del5 mutation (35). Despite the moderate frequency of the Arg215Trp heterozygotes among the Eastern Europe population, to date no NBS cases caused by the homozygosity for the Arg215Trp mutation have been described (28).…”

Section: Discussionmentioning

confidence: 99%

“…Despite the moderate frequency of the Arg215Trp heterozygotes among the Eastern Europe population, to date no NBS cases caused by the homozygosity for the Arg215Trp mutation have been described (28). This leads to the hypothesis that the homozygosity for the Arg215Trp mutation may lead to a very severe phenotype, probably lethal in the early development (35,36).…”

Section: Discussionmentioning

confidence: 99%

“…However, the reason because both the heterozygous carriers of the Arg215Trp NBN mutation and the twin brothers compound heterozygous Arg215Trp/657del5 do not show chromosomal instability remains still unclear (35,56).…”

Section: Discussionmentioning

confidence: 99%

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Cleavage of the BRCT tandem domains of nibrin by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation

et al. 2012

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SummaryThe Nijmegen breakage syndrome (NBS) is a genetic disorder caused by mutations in NBN gene and characterized by chromosomal instability and hypersensitivity to ionizing radiations (IR). The N-terminus of nibrin (NBN) contains a tandem breast cancer 1 (BRCA1) carboxy-terminal (BRCT) domain that represents one of the major mediators of phosphorylation-dependent protein-protein interactions in processes related to cell cycle checkpoint and DNA repair functions. Patients with NBS compound heterozygous for the 657del5 hypomorphic mutation and for the Arg215Trp missense mutation (corresponding to the 643C[T gene mutation) display a clinical phenotype more severe than that of patients homozygous for the 657del5 mutation. Here, we show that both the 657del5 and Arg215Trp mutations, occurring within the tandem BRCT domains of NBN, although not altering the assembly of the MRE11/RAD50/NBN (MRN) complex, affect the MRE11 IR-induced nuclear foci (IRIF) formation and the DNA doublestrand break (DSB) signaling via the phosphorylation of both ataxia-telangiectasia-mutated (ATM) kinase and ATM downstream targets (e.g., SMC1 and p53). Remarkably, data obtained indicate that the cleavage of the BRCT tandem domains of NBN by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation. Indeed, the 70-kDa NBN fragment, arising from the 657del5 mutation, maintains the capability to interact with MRE11 and c-H2AX and to form IRIF. Altogether, the role of the tandem BRCT domains of NBN in the localization of the MRN complex at the DNA DSB and in the activation of the damage response is highlighted.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Cleavage of the BRCT tandem domains of nibrin by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation

et al. 2012

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“…This mutation was described for the first time in patients diagnosed with ALL (23). Previous studies conducted on a Caucasian population demonstrated that p.R215W carriers have an increased risk of non-Hodgkin lymphoma, colorectal, breast and prostate cancer (22,24,25).…”

Section: Discussionmentioning

confidence: 93%

Heterozygous p.I171V mutation of the NBN gene as a risk factor for lung cancer development

et al. 2015

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N ijmegen Breakage Syndrome ( NBS )

2004

Encyclopedic Dictionary of Genetics, Genomics and Proteomics

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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 n...

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Nijmegen breakage syndrome (NBS) with neurological abnormalities and without chromosomal instability

Abstract: Interestingly, the patients are more severely affected than classical NBS patients. Consequently, we postulate that homozygosity for the 643C>T(R215W) mutation will also lead to a, possibly very, severe disease phenotype.

Cited by 45 publications

References 25 publications

Cleavage of the BRCT tandem domains of nibrin by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation

Cleavage of the BRCT tandem domains of nibrin by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation

Heterozygous p.I171V mutation of the NBN gene as a risk factor for lung cancer development

N ijmegen Breakage Syndrome ( NBS )

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