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Krystyna H. Chrzanowska - One of the best experts on this subject based on the ideXlab platform.
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telomere attrition and dysfunction a potential trigger of the progeroid phenotype in Nijmegen Breakage Syndrome
Aging, 2020Co-Authors: Ilja Demuth, Krystyna H. Chrzanowska, Eva Seemanova, Ryong Kim, Heidemarie Neitzel, Raneem Habib, Renaldo Faber, Martin DigweedAbstract:Background Nibrin, as part of the NBN/MRE11/RAD50 complex, is mutated in Nijmegen Breakage Syndrome (NBS), which leads to impaired DNA damage response and lymphoid malignancy. Results Telomere length (TL) was markedly reduced in homozygous patients (and comparably so in all chromosomes) by ~40% (qPCR) and was slightly reduced in NBS heterozygotes older than 30 years (~25% in qPCR), in accordance with the respective cancer rates. Humanized cancer-free NBS mice had normal TL. Telomere elongation was inducible by telomerase and/or alternative telomere lengthening but was associated with abnormal expression of telomeric genes involved in aging and/or cell growth. Lymphoblastoid cells from NBS patients with long survival times (>12 years) displayed the shortest telomeres and low caspase 7 activity. Conclusions NBS is a secondary telomeropathy. The two-edged sword of telomere attrition enhances the cancer-prone situation in NBS but can also lead to a relatively stable cellular phenotype in tumor survivors. Results suggest a modular model for progeroid Syndromes with abnormal expression of telomeric genes as a molecular basis. Methods We studied TL and function in 38 homozygous individuals, 27 heterozygotes, one homozygous fetus, six NBS lymphoblastoid cell lines, and humanized NBS mice, all with the same founder NBN mutation: c.657_661del5.
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correction to circulating t cells of patients with Nijmegen Breakage Syndrome show signs of senescence
Journal of Clinical Immunology, 2018Co-Authors: Ruud W J Meijers, Katarzyna Dzierzanowskafangrat, Magdalena Zborowska, Iwona Solarska, Dennis Tielemans, Bob A C Van Turnhout, Gertjan J Driessen, Mirjam Van Der Burg, Jacques J M Van Dongen, Krystyna H. ChrzanowskaAbstract:The original version of the article, "Circulating T Cells of Patients with Nijmegen Breakage Syndrome Show Signs of Senescence” incorrectly listed the affiliation of the fourth author, Iwona Solarska. The correct affiliation is “Molecular Biology Laboratory, Institute of Hematology and Transfusion Medicine.
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circulating t cells of patients with Nijmegen Breakage Syndrome show signs of senescence
Journal of Clinical Immunology, 2017Co-Authors: Ruud W J Meijers, Katarzyna Dzierzanowskafangrat, Magdalena Zborowska, Iwona Solarska, Dennis Tielemans, Bob A C Van Turnhout, Gertjan J Driessen, Mirjam Van Der Burg, Jacques J M Van Dongen, Krystyna H. ChrzanowskaAbstract:The Nijmegen Breakage Syndrome (NBS) is an inherited genetic disorder characterized by a typical facial appearance, microcephaly, growth retardation, immunodeficiency, and a strong predisposition to malignancies, especially of lymphoid origin. NBS patients have a mutation in the NBN gene which involves the repair of DNA double-strand breaks (DSBs). Here we studied the peripheral T cell compartment of NBS patients with a focus on immunological senescence. The absolute numbers and frequencies of the different T cell subsets were determined in NBS patients from young age till adulthood and compared to age-matched healthy individuals (HI). In addition, we determined the expression of senescent T cell markers and the signal joint T cell receptor excision circles (sjTRECs) content. Our results demonstrate that NBS patients have reduced T cell numbers. NBS patients showed lower numbers of αβ+ T cells, but normal γδ+ T cell numbers compared to HI. Concerning the αβ+ T cells, both CD4+ as well as CD8+ T cells were excessively reduced in numbers compared to aged-matched HI. In addition, NBS patients showed higher frequencies of the more differentiated T cells expressing the senescent cell marker CD57 and did not express co-stimulatory molecule CD28. These effects were already present in the youngest age group. Furthermore, NBS patients showed lower sjTREC content in their T cells possibly indicative of a lower thymic output. We conclude that circulating T cells from NBS patients show signs of a senescent phenotype which is already present from young age on and which might explain their T cell immune deficiency.
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Nijmegen Breakage Syndrome (NBS)
Orphanet journal of rare diseases, 2012Co-Authors: Krystyna H. Chrzanowska, Hanna Gregorek, Bożenna Dembowska-bagińska, Maria Kalina, Martin DigweedAbstract: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.
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high prevalence of primary ovarian insufficiency in girls and young women with Nijmegen Breakage Syndrome evidence from a longitudinal study
The Journal of Clinical Endocrinology and Metabolism, 2010Co-Authors: Krystyna H. Chrzanowska, Hanna Gregorek, Maria Kalina, Maria Szarrasczapnik, Maria Gajdulewicz, Malgorzata Gajtkometera, Malgorzata Walewskawolf, Jolanta Szufladowiczwozniak, Henryk Rysiewski, Bozena CukrowskaAbstract:Context: Nijmegen Breakage Syndrome (NBS) is a severe chromosomal instability disorder characterized by microcephaly, growth retardation, immune deficiency, and predisposition for malignancy. It is caused by hypomorphic mutations in the NBN gene, which product belongs to the protein complex critical for processing DNA double-strand breaks during mitotic and meiotic recombination. Data on gonadal function in patients with NBS are limited. Objective: Growth and sexual development, along with hormonal assays, were evaluated in girls and young women with NBS homozygous for c.657_661del5 mutation. Study Design and Patients: The group comprised 37 girls and young women with NBS (ages, 0.17–24.25 yr), followed between 1993 and 2008. Patients were divided into three age groups: 1) 1–3 yr; 2) 4–9 yr; and 3) 10 yr and older. Growth, puberty, concentrations of gonadotropins and 17-β-estradiol, bone age, and pelvic ultrasound were assessed. Results: None of the patients presented a typical growth spurt; the adult hei...
Martin Digweed - One of the best experts on this subject based on the ideXlab platform.
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telomere attrition and dysfunction a potential trigger of the progeroid phenotype in Nijmegen Breakage Syndrome
Aging, 2020Co-Authors: Ilja Demuth, Krystyna H. Chrzanowska, Eva Seemanova, Ryong Kim, Heidemarie Neitzel, Raneem Habib, Renaldo Faber, Martin DigweedAbstract:Background Nibrin, as part of the NBN/MRE11/RAD50 complex, is mutated in Nijmegen Breakage Syndrome (NBS), which leads to impaired DNA damage response and lymphoid malignancy. Results Telomere length (TL) was markedly reduced in homozygous patients (and comparably so in all chromosomes) by ~40% (qPCR) and was slightly reduced in NBS heterozygotes older than 30 years (~25% in qPCR), in accordance with the respective cancer rates. Humanized cancer-free NBS mice had normal TL. Telomere elongation was inducible by telomerase and/or alternative telomere lengthening but was associated with abnormal expression of telomeric genes involved in aging and/or cell growth. Lymphoblastoid cells from NBS patients with long survival times (>12 years) displayed the shortest telomeres and low caspase 7 activity. Conclusions NBS is a secondary telomeropathy. The two-edged sword of telomere attrition enhances the cancer-prone situation in NBS but can also lead to a relatively stable cellular phenotype in tumor survivors. Results suggest a modular model for progeroid Syndromes with abnormal expression of telomeric genes as a molecular basis. Methods We studied TL and function in 38 homozygous individuals, 27 heterozygotes, one homozygous fetus, six NBS lymphoblastoid cell lines, and humanized NBS mice, all with the same founder NBN mutation: c.657_661del5.
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DNA damage in Nijmegen Breakage Syndrome cells leads to PARP hyperactivation and increased oxidative stress.
PLoS genetics, 2012Co-Authors: Harald Krenzlin, Bastian Salewsky, Petra Wessendorf, Ilja Demuth, Alexander Bürkle, Kathrin Weidele, Martin DigweedAbstract: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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Nijmegen Breakage Syndrome (NBS)
Orphanet journal of rare diseases, 2012Co-Authors: Krystyna H. Chrzanowska, Hanna Gregorek, Bożenna Dembowska-bagińska, Maria Kalina, Martin DigweedAbstract: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.
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Clinical variability and expression of the NBN c.657del5 allele in Nijmegen Breakage Syndrome.
Gene, 2009Co-Authors: Stephan Lins, Lars Krüger, Krystyna H. Chrzanowska, Eva Seemanova, Ryong Kim, Martin DigweedAbstract:Patients affected by the autosomal recessive Nijmegen Breakage Syndrome (NBS [MIM 251260]) have possibly the highest risk for developing a malignancy of all the chromosomal instability Syndromes. This reflects the profound disturbance to genomic integrity and cellular homeostasis that is caused by the mutation of the essential mammalian gene, NBN. Whilst null-mutation of Nbn is lethal in the mouse, NBS patients survive due to the fact that the common human founder mutation, found in over 90% of patients, is in fact hypomorphic and leads, by alternative translation, to varying amounts of a partially functional carboxy-terminal protein fragment, p70-nibrin. The expression level of p70-nibrin correlates with cancer incidence amongst patients. Using real-time PCR we have now found that the variation in p70-nibrin expression cannot be attributed to differences in mRNA quantity and that nonsense-mediated mRNA decay is not responsible for the observed variation. We discuss an alternative explanation for p70-nibrin expression variation.
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the clinical manifestation of a defective response to dna double strand breaks as exemplified by Nijmegen Breakage Syndrome
Oncogene, 2007Co-Authors: Ilja Demuth, Martin DigweedAbstract:The autosomal recessive genetic disorder Nijmegen Breakage Syndrome (NBS) was first described in 1981 in patients living in Nijmegen, Holland. NBS patients display a characteristic facial appearance, microcephaly and a range of symptoms including immunodeficiency, increased cancer risk and growth retardation. In addition, NBS patient cells were found to have elevated levels of chromosomal damage and to be sensitive to ionizing irradiation (IR). This radiosensitivity had fatal consequences in some undiagnosed patients. The most dangerous DNA lesion caused by IR is considered to be the double-strand break (DSB) and indeed, NBS patient cells are sensitive to all mutagens that produce DSBs directly or indirectly. We discuss here our current understanding of how a deficiency in DSB repair manifests as the particular symptom complex of NBS.
Karl Sperling - One of the best experts on this subject based on the ideXlab platform.
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mild Nijmegen Breakage Syndrome phenotype due to alternative splicing
Human Molecular Genetics, 2006Co-Authors: Raymonda Varon, Antonio Antoccia, Veronique Dutrannoy, Georg Weikert, C Tanzarella, Lars Stockl, Emanuela Spadoni, Larsarne Kruger, Alessandra Di Masi, Karl SperlingAbstract:Hypomorphic mutations of the NBS1 gene are responsible for Nijmegen Breakage Syndrome (NBS), characterized by microcephaly, chromosomal instability, radiosensitivity, immunodeficiency and high cancer predisposition. Over 90% of NBS patients are homozygous for the 657Delta5 mutation and are of Slavic origin; however, 10 further truncating mutations have been identified in patients of other ethnic origin. Partially functional proteins produced by alternative initiation of translation, and possibly diminishing the severity of the NBS phenotype, have been described for several NBS1 mutations. Here, we report a 53-year-old NBS patient, homozygous for the NBS1 mutation, 742insGG, in exon 7 and who presents with a particularly mild phenotype. In an attempt to find a potential molecular explanation for the mild phenotype observed, we carried out a conventional semi-quantitative and quantitative RT-PCR analyses which revealed two transcripts of almost equal amounts in the patient and her parents--the expected full-length transcript carrying the 742insGG mutation and a second transcript with deleted exons 6 and 7. The transcript was also observed in controls and other NBS patients, however, at quantities more than 100-fold lower than that in the patient described here. Because the skipping of exons 6 and 7 results in an internal in-frame deletion, which eliminates the truncating GG-insertion, we propose that this transcript may code for a partially functional protein of approximately 70 kDa that could be responsible for the unusually mild NBS phenotype observed in this patient. Indeed, complementation analysis of null-mutant mouse cells indicates that the alternatively spliced mRNA codes for a protein with significant functional capacity.
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Nijmegen Breakage Syndrome (NBS) with neurological abnormalities and without chromosomal instability
Journal of medical genetics, 2005Co-Authors: Eva Seemanova, Pavel Seeman, Karl Sperling, Raymonda Varon, Heidemarie Neitzel, Jan Hadac, Olga Butova, Evelin Schröck, Martin DigweedAbstract:Background: Nijmegen Breakage Syndrome (NBS) is an autosomal recessive chromosomal instability disorder with hypersensitivity to ionising radiation. The clinical phenotype is characterised by congenital microcephaly, mild dysmorphic facial appearance, growth retardation, immunodeficiency, and greatly increased risk for lymphoreticular malignancy. Most NBS patients are of Slavic origin and homozygous for the founder mutation 657del5. The frequency of 657del5 heterozygotes in the Czech population is 1:150. Recently, another NBS1 mutation, 643C>T(R215W), with uncertain pathogenicity was found to have higher frequency among tumour patients of Slavic origin than in controls. This alteration results in the substitution of the basic amino acid arginine with the non-polar tryptophan and thus could potentially interfere with the function of the NBS1 protein, nibrin. Methods and Results: Children with congenital microcephaly are routinely tested for the 657del5 mutation in the Czech and Slovak Republics. Here, we describe for the first time a severe form of NBS without chromosomal instability in monozygotic twin brothers with profound congenital microcephaly and developmental delay who are compound heterozygotes for the 657del5 and 643C>T(R215W) NBS1 mutations. Both children showed reduced expression of full length nibrin when compared with a control and a heterozygote for the 657del5 mutation. Radiation response processes such as phosphorylation of ATM and phosphorylation/stabilisation of p53, which are promoted by NBS1, are strongly reduced in cells from these patients. Conclusions: 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.
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Nijmegen Breakage Syndrome: clinical manifestation of defective response to DNA double-strand breaks
DNA Repair, 2004Co-Authors: Martin Digweed, Karl SperlingAbstract:Nijmegen Breakage Syndrome is a rare autosomal recessive genetic disease belonging to a group of disorders often called chromosome instability Syndromes. In addition to a characteristic facial appearance and microcephaly, patients suffering from Nijmegen Breakage Syndrome have a range of symptoms including radiosensitivity, immunodeficiency, increased cancer risk and growth retardation. The underlying gene, NBS1, is located on human chromosome 8q21 and codes for a protein product termed nibrin, Nbs1 or p95. Over 90% of patients are homozygous for a founder mutation: a deletion of five base pairs which leads to a framehift and protein truncation. The protein nibrin/Nbs1 is suspected to be involved in the cellular response to DNA damage caused by ionising irradiation, thus accounting for the radiosensitivity of Nijmegen Breakage Syndrome. We review here some of the more recent findings on the NBS1 gene and discuss how they impinge on the clinical manifestation of the disease.
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Nijmegen Breakage Syndrome in 13 of age matched czech children with primary microcephaly
Pediatric Neurology, 2004Co-Authors: Pavel Seeman, Kateřina Gebertova, Kateřina Paděrova, Karl Sperling, Eva SeemanovaAbstract:The Nijmegen Breakage Syndrome is a rare autosomal recessive chromosomal instability disorder characterized by early growth retardation, congenital microcephaly, immunodeficiency, borderline mental development, and a high tendency to lymphoreticular malignancies. Most Nijmegen Breakage Syndrome patients are of Slavonic origin, and all of them known so far carry a founder homozygous 5 nucleotide deletion in the NBS1 gene. Microcephaly was present in 100% of Nijmegen Breakage Syndrome patients in a recent large international cooperative study. The frequency of Nijmegen Breakage Syndrome among children with primary microcephaly was not known. Early correct diagnosis of the Syndrome is crucial for appropriate preventive care and therapy. We tested 67 Czech patients of different ages with simple microcephaly for the presence of the most common mutation in the NBS1 gene. Three new Nijmegen Breakage Syndrome cases were detected in this cohort, representing 4.5% of the cohort. All these newly diagnosed Nijmegen Breakage Syndrome patients were younger than 10 months at the time of diagnosis. They were all born within a 2.5-year period. Twenty-three of the 67 children in the cohort were born within this 2.5-year period, representing a 13% incidence of Nijmegen Breakage Syndrome. Frequency of Nijmegen Breakage Syndrome heterozygotes among infants in the Czech Republic is 1: 130-158 and the birth rate is 90,000 per year, therefore in the time span of 2.5 years, three new Nijmegen Breakage Syndrome homozygotes are expected to be born. Therefore we assume that by DNA testing of Czech primary microcephalic children it is possible to detect all Nijmegen Breakage Syndrome patients to be expected. The age at correct diagnosis was lowered from 7.1 years at the time before DNA testing, to well under 1 year of age. All new Nijmegen Breakage Syndrome patients could receive appropriate preventive care, which should significantly improve their life expectancy and prognosis.
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Mutations in the Nijmegen Breakage Syndrome Gene (NBS1) in Childhood Acute Lymphoblastic Leukemia (ALL)
Cancer research, 2001Co-Authors: Raymonda Varon, Karl Sperling, Andre Reis, Günter Henze, Hagen Graf V. Einsiedel, Karlheinz SeegerAbstract:The Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive disorder associated with immune deficiency, chromosome fragility, and increased susceptibility to lymphoid malignancies. The aim of the present study was to elucidate the potential role of the gene mutated in NBS (NBS1) in the pathogenesis and disease progression of childhood acute lymphoblastic leukemia (ALL). Samples from 47 children with first relapse of ALL were analyzed for mutations in all 16 exons of the NBS1 gene, and in 7 of them (14.9%), four novel amino acid substitutions were identified. Mutations S93L, D95N, and I171V occur in the two known domains of nibrin that are probably involved in protein-protein interactions. Germ-line origin of the I171V mutation was confirmed in three patients, whereas the D95N exchange was present only in leukemic cells. The R215W mutation was observed in one ALL but also in a population-based study and probably represents a rare sequence variant. No additional mutations were found on the second allele in any of these seven patients. The observed NBS1 gene mutations in ALL patients points to its possible involvement in the pathogenesis of this disease.
Richard A Gatti - One of the best experts on this subject based on the ideXlab platform.
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Nijmegen Breakage Syndrome detected by newborn screening for t cell receptor excision circles trecs
The Journal of Allergy and Clinical Immunology, 2015Co-Authors: Jay Patel, Richard A Gatti, Jennifer M Puck, Kunal Kundu, Uma Sunderam, Christina Brown, Rajgopal Srinivasan, Steven E Brenner, Joseph A ChurchAbstract:Purpose Severe combined immunodeficiency (SCID) encompasses a group of disorders characterized by reduced or absent T-cell number and function and identified by newborn screening utilizing T-cell receptor excision circles (TRECs). This screening has also identified infants with T lymphopenia who lack mutations in typical SCID genes. We report an infant with low TRECs and non-SCID T lymphopenia, who proved upon whole exome sequencing to have Nijmegen Breakage Syndrome (NBS).
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ORIGINAL RESEARCH Nijmegen Breakage Syndrome Detected by Newborn Screening for T Cell Receptor Excision Circles (TRECs)
2014Co-Authors: Jay P. Patel, Richard A Gatti, Jennifer M Puck, Kunal Kundu, Uma Sunderam, Christina Brown, Rajgopal Srinivasan, Steven E Brenner, Joseph A ChurchAbstract:Purpose Severe combined immunodeficiency (SCID) en-compasses a group of disorders characterized by reduced or absent T-cell number and function and identified by newborn screening utilizing T-cell receptor excision circles (TRECs). This screening has also identified infants with T lymphopenia who lackmutations in typical SCID genes.We report an infant with low TRECs and non-SCID T lymphopenia, who proved upon whole exome sequencing to have Nijmegen Breakage Syndrome (NBS). Methods Exome sequencing of DNA from the infant and his parents was performed. Genomic analysis revealed deleteri-ous variants in the NBN gene. Confirmatory testing included Sanger sequencing and immunoblotting and radiosensitivity testing of patient lymphocytes. Results Two novel nonsense mutations in NBN were identi-fied in genomic DNA from the family. Immunoblotting showed absence of nibrin protein. A colony survival assay demonstrated radiosensitivity comparable to patients with ataxia telangiectasia. Conclusions Although TREC screening was developed to identify newborns with SCID, it has also identified T lympho-penic disorders that may not otherwise be diagnosed until later in life. Timely identification of an infant with T lymphopenia allowed for prompt pursuit of underlying etiology, making possible a diagnosis of NBS, genetic counseling, and early intervention to minimize complications
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medulloblastoma with adverse reaction to radiation therapy in Nijmegen Breakage Syndrome
Journal of Pediatric Hematology Oncology, 2003Co-Authors: Sameer Bakhshi, Richard A Gatti, Karen M Cerosaletti, Patrick Concannon, Erawati V Bawle, James Fontanesi, Kanta BhambhaniAbstract:A 3-year-old child with microcephaly, facial dysmorphism, growth retardation, and developmental delay was diagnosed with medulloblastoma. Craniospinal irradiation resulted in severe radiation-induced dermatitis and gastroesophagitis, unresponsive to further medical therapy. Colony survival assay on the patient's transformed lymphocytes revealed a high degree of radiosensitivity ex vivo. The presence of radiation sensitivity, both clinically and ex vivo, in association with microcephaly and growth retardation, prompted a diagnostic workup for Nijmegen Breakage Syndrome. The patient was confirmed to have a compound heterozygote genotype for the common founder mutation of NBS1 675del5 in exon 6, and 1142delC in exon 10. Because irradiation is an important component of therapy for brain tumors, caution should be exercised in cancer patients with associated microcephaly and growth retardation, as they may turn out to have the rare diagnosis of Nijmegen Breakage Syndrome.
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Nijmegen Breakage Syndrome clinical characteristics and mutation analysis in eight unrelated russian families
The Journal of Pediatrics, 2002Co-Authors: Igor B Resnick, Irina Kondratenko, Richard A Gatti, Karen M Cerosaletti, Oleg Togoev, Natalia Vasserman, Irena Shagina, Oleg Evgrafov, Svetlana Tverskaya, Patrick ConcannonAbstract:Abstract Objective: The purpose of the study was to ascertain patients with Nijmegen Breakage Syndrome (NBS) in the Russian population and characterize the clinical phenotype and molecular genotype of these patients. Study design: Eight unrelated Russian patients with possible diagnoses of NBS were identified. Family histories were collected and clinical and laboratory analyses were carried out. Mutation screening of the NBS1 gene was carried out to confirm the diagnosis in 7 cases. Results: All patients had the key diagnostic features of NBS. One patient had acute myeloblastic leukemia (AML). Two patients had bone marrow aplasia, not previously described as a feature of NBS. Mutation screening of the NBS1 gene revealed that 6 patients were homozygous for the 657del5 mutation, whereas a seventh patient was a compound heterozygote, having the 657del5 mutation and an additional novel mutation, 681delT. Conclusions: Molecular analyses confirmed the diagnosis of NBS in 7 of the patients. The surprising finding of bone marrow aplasia or AML in 3 of 7 patients raises the possibility of a connection between NBS and another DNA damage disorder, Fanconi anemia. (J Pediatr 2002;140:355-61)
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V(D)J rearrangement in Nijmegen Breakage Syndrome.
Molecular immunology, 2000Co-Authors: Tiong Chia Yeo, Karl Sperling, Richard A Gatti, Patrick Concannon, Dong Xia, Samar Hassouneh, Xuexian O. Yang, Daniel E. Sabath, Dennis M. WillerfordAbstract:Abstract Repair of DNA double-strand breaks is essential for maintenance of genomic stability, and is specifically required for rearrangement of immunoglobulin (Ig) and T cell receptor (TCR) loci during development of the immune system. Abnormalities in these repair processes also contribute to oncogenic chromosomal rearrangements that underlie many lymphoid malignancies. Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive condition characterized by immunodeficiency, radiation sensitivity, and increased predisposition to lymphoid cancers bearing oncogenic Ig and TCR locus translocations. NBS patients fail to produce nibrin, a protein required for the nuclear localization and function of a DNA repair complex that includes Mre11 and Rad50. Mre11 has biochemical properties that suggest a potential role in V(D)J recombination. We studied V(D)J recombination in NBS cells in vitro and in vivo, using cell lines and peripheral blood leukocyte DNA from NBS patients. We found that NBS cells were competent to rejoin signal substrates with normal efficiency and high fidelity. Coding substrates were similarly rejoined efficiently, and coding end structures appeared normal. In B cells from NBS patients, the spectrums of IgH CDR3 regions were diverse and normally distributed. Moreover, the lengths and composition of Igκ VJ joins and IgH VDJ joins derived from NBS and normal subjects were indistinguishable. Our data indicate that nibrin plays no essential role in V(D)J recombination and is not required for the generation of an apparently diverse B cell repertoire.
Raymonda Varon - One of the best experts on this subject based on the ideXlab platform.
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Human RAD50 deficiency in a Nijmegen Breakage Syndrome-like disorder.
American journal of human genetics, 2009Co-Authors: Regina Waltes, Markus Stumm, Raymonda Varon, Reinhard Kalb, Magtouf Gatei, Amanda W. Kijas, Alexandra Sobeck, Britta Wieland, Yaniv Lerenthal, Martin F. LavinAbstract:The MRE11/RAD50/NBN (MRN) complex plays a key role in recognizing and signaling DNA double-strand breaks (DSBs). Hypomorphic mutations in NBN (previously known as NBS1) and MRE11A give rise to the autosomal-recessive diseases Nijmegen Breakage Syndrome (NBS) and ataxia-telangiectasia-like disorder (ATLD), respectively. To date, no disease due to RAD50 deficiency has been described. Here, we report on a patient previously diagnosed as probably having NBS, with microcephaly, mental retardation, ‘bird-like’ face, and short stature. At variance with this diagnosis, she never had severe infections, had normal immunoglobulin levels, and did not develop lymphoid malignancy up to age 23 years. We found that she is compound heterozygous for mutations in the RAD50 gene that give rise to low levels of unstable RAD50 protein. Cells from the patient were characterized by chromosomal instability; radiosensitivity; failure to form DNA damage-induced MRN foci; and impaired radiation-induced activation of and downstream signaling through the ATM protein, which is defective in the human genetic disorder ataxia-telangiectasia. These cells were also impaired in G1/S cell-cycle-checkpoint activation and displayed radioresistant DNA synthesis and G2-phase accumulation. The defective cellular phenotype was rescued by wild-type RAD50. In conclusion, we have identified and characterized a patient with a RAD50 deficiency that results in a clinical phenotype that can be classified as an NBS-like disorder (NBSLD).
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mild Nijmegen Breakage Syndrome phenotype due to alternative splicing
Human Molecular Genetics, 2006Co-Authors: Raymonda Varon, Antonio Antoccia, Veronique Dutrannoy, Georg Weikert, C Tanzarella, Lars Stockl, Emanuela Spadoni, Larsarne Kruger, Alessandra Di Masi, Karl SperlingAbstract:Hypomorphic mutations of the NBS1 gene are responsible for Nijmegen Breakage Syndrome (NBS), characterized by microcephaly, chromosomal instability, radiosensitivity, immunodeficiency and high cancer predisposition. Over 90% of NBS patients are homozygous for the 657Delta5 mutation and are of Slavic origin; however, 10 further truncating mutations have been identified in patients of other ethnic origin. Partially functional proteins produced by alternative initiation of translation, and possibly diminishing the severity of the NBS phenotype, have been described for several NBS1 mutations. Here, we report a 53-year-old NBS patient, homozygous for the NBS1 mutation, 742insGG, in exon 7 and who presents with a particularly mild phenotype. In an attempt to find a potential molecular explanation for the mild phenotype observed, we carried out a conventional semi-quantitative and quantitative RT-PCR analyses which revealed two transcripts of almost equal amounts in the patient and her parents--the expected full-length transcript carrying the 742insGG mutation and a second transcript with deleted exons 6 and 7. The transcript was also observed in controls and other NBS patients, however, at quantities more than 100-fold lower than that in the patient described here. Because the skipping of exons 6 and 7 results in an internal in-frame deletion, which eliminates the truncating GG-insertion, we propose that this transcript may code for a partially functional protein of approximately 70 kDa that could be responsible for the unusually mild NBS phenotype observed in this patient. Indeed, complementation analysis of null-mutant mouse cells indicates that the alternatively spliced mRNA codes for a protein with significant functional capacity.
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Nijmegen Breakage Syndrome (NBS) with neurological abnormalities and without chromosomal instability
Journal of medical genetics, 2005Co-Authors: Eva Seemanova, Pavel Seeman, Karl Sperling, Raymonda Varon, Heidemarie Neitzel, Jan Hadac, Olga Butova, Evelin Schröck, Martin DigweedAbstract:Background: Nijmegen Breakage Syndrome (NBS) is an autosomal recessive chromosomal instability disorder with hypersensitivity to ionising radiation. The clinical phenotype is characterised by congenital microcephaly, mild dysmorphic facial appearance, growth retardation, immunodeficiency, and greatly increased risk for lymphoreticular malignancy. Most NBS patients are of Slavic origin and homozygous for the founder mutation 657del5. The frequency of 657del5 heterozygotes in the Czech population is 1:150. Recently, another NBS1 mutation, 643C>T(R215W), with uncertain pathogenicity was found to have higher frequency among tumour patients of Slavic origin than in controls. This alteration results in the substitution of the basic amino acid arginine with the non-polar tryptophan and thus could potentially interfere with the function of the NBS1 protein, nibrin. Methods and Results: Children with congenital microcephaly are routinely tested for the 657del5 mutation in the Czech and Slovak Republics. Here, we describe for the first time a severe form of NBS without chromosomal instability in monozygotic twin brothers with profound congenital microcephaly and developmental delay who are compound heterozygotes for the 657del5 and 643C>T(R215W) NBS1 mutations. Both children showed reduced expression of full length nibrin when compared with a control and a heterozygote for the 657del5 mutation. Radiation response processes such as phosphorylation of ATM and phosphorylation/stabilisation of p53, which are promoted by NBS1, are strongly reduced in cells from these patients. Conclusions: 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.
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radiosensitivity of ataxia telangiectasia and Nijmegen Breakage Syndrome homozygotes and heterozygotes as determined by three color fish chromosome painting
Radiation Research, 2002Co-Authors: Susann Neubauer, Rouben Arutyunyan, Markus Stumm, Thilo Dork, Regina Bendix, Michael Bremer, Raymonda Varon, Rolf Sauer, Erich GebhartAbstract:Abstract Neubauer, S., Arutyunyan, R., Stumm, M., Dork, T., Bendix, R., Bremer, M., Varon, R., Sauer, R. and Gebhart, E. Radiosensitivity of Ataxia Telangiectasia and Nijmegen Breakage Syndrome Homozygotes and Heterozygotes as Determined by Three-Color FISH Chromosome Painting. Radiat. Res. 157, 312 – 321 (2002). A three-color chromosome painting technique was used to examine the spontaneous and radiation-induced chromosomal damage in peripheral lymphocytes and lymphoblastoid cells from 11 patients with ataxia telangiectasia (AT) and from 14 individuals heterozygous for an AT allele. In addition, cells from two homozygous and six obligate heterozygous carriers of mutations in the Nijmegen Breakage Syndrome gene (NBS) were investigated. The data were compared to those for chromosome damage in 10 unaffected control individuals and 48 cancer patients who had not yet received therapeutic treatment. Based on the well-documented radiation sensitivity of AT and NBS patients, it was of particular interest to dete...
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Mutations in the Nijmegen Breakage Syndrome Gene (NBS1) in Childhood Acute Lymphoblastic Leukemia (ALL)
Cancer research, 2001Co-Authors: Raymonda Varon, Karl Sperling, Andre Reis, Günter Henze, Hagen Graf V. Einsiedel, Karlheinz SeegerAbstract:The Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive disorder associated with immune deficiency, chromosome fragility, and increased susceptibility to lymphoid malignancies. The aim of the present study was to elucidate the potential role of the gene mutated in NBS (NBS1) in the pathogenesis and disease progression of childhood acute lymphoblastic leukemia (ALL). Samples from 47 children with first relapse of ALL were analyzed for mutations in all 16 exons of the NBS1 gene, and in 7 of them (14.9%), four novel amino acid substitutions were identified. Mutations S93L, D95N, and I171V occur in the two known domains of nibrin that are probably involved in protein-protein interactions. Germ-line origin of the I171V mutation was confirmed in three patients, whereas the D95N exchange was present only in leukemic cells. The R215W mutation was observed in one ALL but also in a population-based study and probably represents a rare sequence variant. No additional mutations were found on the second allele in any of these seven patients. The observed NBS1 gene mutations in ALL patients points to its possible involvement in the pathogenesis of this disease.