Impaired p53-Mediated DNA Damage Response Contributes to Microcephaly in Nijmegen Breakage Syndrome Patient-Derived Cerebral Organoids
Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive genetic disorder caused by mutations within nibrin (<i>NBN</i>), a DNA damage repair protein. Hallmarks of NBS include chromosomal instability and clinical manifestations such as growth retardation, immunodeficiency, and prog...
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MDPI AG
2022-02-01
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| author | Soraia Martins Lars Erichsen Angeliki Datsi Wasco Wruck Wolfgang Goering Eleftheria Chatzantonaki Vanessa Cristina Meira de Amorim Andrea Rossi Krystyna H. Chrzanowska James Adjaye |
| author_facet | Soraia Martins Lars Erichsen Angeliki Datsi Wasco Wruck Wolfgang Goering Eleftheria Chatzantonaki Vanessa Cristina Meira de Amorim Andrea Rossi Krystyna H. Chrzanowska James Adjaye |
| author_sort | Soraia Martins |
| collection | DOAJ |
| description | Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive genetic disorder caused by mutations within nibrin (<i>NBN</i>), 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 <i>NBN</i> 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 <i>NBN</i> alters neurogenesis in NBS patients, thus providing a proof of concept that cerebral organoids are a valuable tool for studying DNA damage-related disorders. |
| first_indexed | 2024-03-09T20:43:25Z |
| format | Article |
| id | doaj.art-190926a79a5c426c8977b04f456875ce |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T20:43:25Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj.art-190926a79a5c426c8977b04f456875ce2023-11-23T22:50:32ZengMDPI AGCells2073-44092022-02-0111580210.3390/cells11050802Impaired p53-Mediated DNA Damage Response Contributes to Microcephaly in Nijmegen Breakage Syndrome Patient-Derived Cerebral OrganoidsSoraia Martins0Lars Erichsen1Angeliki Datsi2Wasco Wruck3Wolfgang Goering4Eleftheria Chatzantonaki5Vanessa Cristina Meira de Amorim6Andrea Rossi7Krystyna H. Chrzanowska8James Adjaye9Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University, 40225 Düsseldorf, GermanyInstitute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University, 40225 Düsseldorf, GermanyInstitute for Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine University, 40225 Düsseldorf, GermanyInstitute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University, 40225 Düsseldorf, GermanyInstitute for Pathology, Medical Faculty, Heinrich-Heine University, 40225 Düsseldorf, GermanyInstitute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University, 40225 Düsseldorf, GermanyInstitute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University, 40225 Düsseldorf, GermanyIUF-Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, GermanyDepartment of Medical Genetics, Children’s Memorial Health Institute, 04-730 Warsaw, PolandInstitute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University, 40225 Düsseldorf, GermanyNijmegen Breakage Syndrome (NBS) is a rare autosomal recessive genetic disorder caused by mutations within nibrin (<i>NBN</i>), 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 <i>NBN</i> 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 <i>NBN</i> alters neurogenesis in NBS patients, thus providing a proof of concept that cerebral organoids are a valuable tool for studying DNA damage-related disorders.https://www.mdpi.com/2073-4409/11/5/802iPSCscerebral organoidsdisease modelingp53NeuronatinNBS |
| spellingShingle | Soraia Martins Lars Erichsen Angeliki Datsi Wasco Wruck Wolfgang Goering Eleftheria Chatzantonaki Vanessa Cristina Meira de Amorim Andrea Rossi Krystyna H. Chrzanowska James Adjaye Impaired p53-Mediated DNA Damage Response Contributes to Microcephaly in Nijmegen Breakage Syndrome Patient-Derived Cerebral Organoids Cells iPSCs cerebral organoids disease modeling p53 Neuronatin NBS |
| title | Impaired p53-Mediated DNA Damage Response Contributes to Microcephaly in Nijmegen Breakage Syndrome Patient-Derived Cerebral Organoids |
| title_full | Impaired p53-Mediated DNA Damage Response Contributes to Microcephaly in Nijmegen Breakage Syndrome Patient-Derived Cerebral Organoids |
| title_fullStr | Impaired p53-Mediated DNA Damage Response Contributes to Microcephaly in Nijmegen Breakage Syndrome Patient-Derived Cerebral Organoids |
| title_full_unstemmed | Impaired p53-Mediated DNA Damage Response Contributes to Microcephaly in Nijmegen Breakage Syndrome Patient-Derived Cerebral Organoids |
| title_short | Impaired p53-Mediated DNA Damage Response Contributes to Microcephaly in Nijmegen Breakage Syndrome Patient-Derived Cerebral Organoids |
| title_sort | impaired p53 mediated dna damage response contributes to microcephaly in nijmegen breakage syndrome patient derived cerebral organoids |
| topic | iPSCs cerebral organoids disease modeling p53 Neuronatin NBS |
| url | https://www.mdpi.com/2073-4409/11/5/802 |
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