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Chromosomal Instability and Molecular Defects in Induced Pluripotent Stem Cells with Nijmegen Breakage Syndrome

ABSTRACT: Nijmegen breakage syndrome (NBS) results from the absence of the NBS1 protein, responsible for detection of DNA double-strand breaks (DSBs). NBS is characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. Here we show successful reprogramming of NBS fibroblasts into induced pluripotent stem cells (NBS-iPSCs). Our data suggest a strong selection for karyotypically normal fibroblasts to go through the reprogramming process. NBS-iPSCs then acquire numerous chromosomal aberrations and show a delayed response to DSB induction. Furthermore, NBS-iPSCs display slower growth, mitotic inhibition, a reduced apoptotic response to stress and abnormal cell cycle-related gene expression. Importantly, NBS neural progenitor cells (NBS-NPCs) show down-regulation of neural developmental genes, which seems to be mediated by P53. Our results demonstrate the importance of NBS1 in early human development, shed new light on the molecular mechanisms underlying this severe syndrome and further expand our knowledge of the genomic stress cells experience during the reprogramming process.

ORGANISM(S): Homo sapiens

PROVIDER: GSE83686 | GEO | 2016/07/19

SECONDARY ACCESSION(S): PRJNA329525

REPOSITORIES: GEO

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Chromosomal Instability and Molecular Defects in Induced Pluripotent Stem Cells with Nijmegen Breakage Syndrome

Project description:Nijmegen breakage syndrome (NBS) results from the absence of the NBS1 protein, responsible for detection of DNA double-strand breaks (DSBs). NBS is characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. Here we show successful reprogramming of NBS fibroblasts into induced pluripotent stem cells (NBS-iPSCs). Our data suggest a strong selection for karyotypically normal fibroblasts to go through the reprogramming process. NBS-iPSCs then acquire numerous chromosomal aberrations and show a delayed response to DSB induction. Furthermore, NBS-iPSCs display slower growth, mitotic inhibition, a reduced apoptotic response to stress and abnormal cell cycle-related gene expression. Importantly, NBS neural progenitor cells (NBS-NPCs) show down-regulation of neural developmental genes, which seems to be mediated by P53. Our results demonstrate the importance of NBS1 in early human development, shed new light on the molecular mechanisms underlying this severe syndrome and further expand our knowledge of the genomic stress cells experience during the reprogramming process. Gene expression analysis was performed on a total of 6 human cell lines, including WT and NBS Neural progenitor cells (NPCs) and NBS-iPSCs

2016-07-19 | E-GEOD-83686 | biostudies-arrayexpress

Heterozygous carriers of Nijmegen Breakage Syndrome Have a Distinct Gene Expression Phenotype.

2006-07-26 | GSE3894 | GEO

Transcription profiling of human heterozygous carriers of Nijmegen Breakage Syndrome reveals distinct gene expression phenotype.

Project description:By comparing the expression levels of genes between carriers of Nijmegen Breakage Syndrome and non-carriers, we showed that NBS carriers have a distinct gene expression phenotype. Experiment Overall Design: Gene expression analysis using Affymetrix Human Focus arrays; comparison of expression levels of genes using t-statistic and identification of genes that allow classification of individuals as carriers or non-carriers by linear discriminant analysis.

2008-06-12 | E-GEOD-3894 | biostudies-arrayexpress

Chromosomal instability associated with adverse outcome: a case report of patient with Nijmegen breakage syndrome and rapidly developed T-NHL with complex karyotype

Project description:Nijmegen breakage syndrome (NBS) is a rare genetic disorder inherited in an autosomal recessive pattern associated with an increased risk of developing lymphoproliferative disorders, mainly non-Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL). This work presents a patient previously diagnosed with Nijmegen breakage syndrome who rapidly developed T-NHL despite of constant medical supervision. Cytogenetic karyotype and microarray tests revealed complex aberrations, indicating enhanced chromosomal instability.

2020-04-07 | GSE148229 | GEO

Molecular and pathological characterisation of diffuse large B-cell lymphomas in children with Nijmegen breakage syndrome

Project description:Nijmegen-breakage syndrome (NBS, OMIM #251260) is an autosomal recessive chromosomal instability syndrome characterized by a very distinct phenotype (microcephaly, growth retardation, immunodeficiency) associated with increased predisposition to develop malignancies, particularly of lymphoid origin (by the age of 20 years, over 40% of NBS patients develop cancer). Immunological lineage of lymphomas in NBS significantly differs from Non-Hodgkin Lymphomas (NHL) entities observed in general pediatric population as well as in primary immunodeficiencies. There is a strong predominance of diffuse large B-cell lymphoma (DLBCL) and T cell lymphoblastic lymphoma (T-LBL/ALL), all showing clonal Ig/TCR rearrangements. In the current study we aimed to examined gene expression signature of metabolic pathways in DLBCL cells.

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Impaired p53-Mediated DNA Damage Response Contributes to Microcephaly in Nijmegen Breakage Syndrome Patient-Derived Cerebral Organoids

Project description:Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive genetic disorder caused by mutations within nibrin (NBN), a DNA damage repair protein. Hallmarks of NBS include chromosomal instability and clinical manifestations such as growth retardation, immunodeficiency, and progressive microcephaly. We employed induced pluripotent stem cell-derived cerebral organoids from two NBS patients to study the etiology of microcephaly. We show that NBS organoids carrying the homozygous 657del5 NBN mutation are significantly smaller with disrupted cyto-architecture. The organoids exhibit premature differentiation, and Neuronatin (NNAT) over-expression. Furthermore, pathways related to DNA damage response and cell cycle are differentially regulated compared to controls. After exposure to bleomycin, NBS organoids undergo delayed p53-mediated DNA damage response and aberrant trans-synaptic signaling, which ultimately leads to neuronal apoptosis. Our data provide insights into how mutations within NBN alters neurogenesis in NBS patients, thus providing a proof of concept that cerebral organoids are a valuable tool for studying DNA damage-related disorders.

2024-10-17 | GSE279611 | GEO

iPSCs from patients with NBS as a model uncovering disease mechanisms and a screening platform for anti-oxidants modifying genomic stability [iPSCs]

Project description:Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive genetic disorder, first described 1981 in Nijmegen, Holland. The characteristics of NBS include genomic instability (resulting in early onset of malignancies), premature aging, microcephaly and other growth retardations, immune deficiency, and impaired puberty and fertility in females. The consequence of these manifestations is a severe decrease in average life span, caused by cancer or infection of the respiratory and urinary tract. We reprogrammed fibroblasts from NBS patients into induced pluripotent stem cells (iPSCS) to bypass premature senescence and to generate an unlimited cell source for modeling purposes. We screened the influence of antioxidants on intracellular levels of ROS and DNA damage and found that EDHB was able to decrease DNA damage in the presence of high oxidative stress. Furthermore, we found that NBS fibroblasts, but not NBS-iPSCs were more susceptible to the induction of DNA damage than their normal counterparts. We performed global transcriptome analysis comparing NBS to normal fibroblasts and NBS-iPSCs to hESCs. There, we found, that TP53 was activated and cell cycle genes broadly down-regulated in NBS fibroblasts and up-regulation of glycolysis specifically in NBS-iPSCs.

2017-08-18 | GSE94707 | GEO

iPSCs from patients with NBS as a model uncovering disease mechanisms and a screening platform for anti-oxidants modifying genomic stability [fibroblasts]

2017-08-18 | GSE94706 | GEO

Genome-wide expression analysis in murine liver after Nbs1 induced knockout

Project description:NBS1 (Nbn in Mus musculus) is a critical component of the MRN (MRE11/RAD50/NBS1) complex, which regulates ATM- and ATR-mediated DNA damage response (DDR) pathways. NBS1 mutations cause the human genomic instability syndrome Nijmegen Breakage Syndrome (NBS), in which microcephaly and intellectual disability are marked neuronal deficits. NBS1 is essential for life, because of its function in the DDR to ensure proliferation and preventing the cell death of replicating cells. However, the function of NBS1 in postmitotic cells is unclear. To explore the possible role of Nbs1 in non-dividing cells and the effection of its deletion on gene expression, RNA-seq was carried out with Nbs1 induced knockout liver samples, in which most cells are postmitotic.

2022-09-16 | GSE137505 | GEO

Genome-wide expression analysis in murine brain in E14.5 vs. 10.5m old mice

Project description:NBS1 (Nbn in Mus musculus) is a critical component of the MRN (MRE11/RAD50/NBS1) complex, which regulates ATM- and ATR-mediated DNA damage response (DDR) pathways. NBS1 mutations cause the human genomic instability syndrome Nijmegen Breakage Syndrome (NBS), in which microcephaly and intellectual disability are marked neuronal deficits. NBS1 is essential for life, because of its function in the DDR to ensure proliferation and preventing the cell death of replicating cells. However, the function of NBS1 in postmitotic cells is unclear. To explore the possible role of Nbs1 in non-dividing cells and the effection of its deletion on gene expression, RNA-seq was carried out to compare the expression of Nbs1 and other DDR molecules in developing and adult brain.

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