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 (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.

Automated summary

This study utilized induced pluripotent stem cell-derived cerebral organoids from Nijmegen Breakage Syndrome (NBS) patients to investigate the etiology of microcephaly. The findings revealed that NBS organoids carrying specific NBN mutations showed smaller size, disrupted cyto-architecture, premature differentiation, and over-expression of Neuronatin (NNAT). Additionally, DNA damage response and cell cycle-related pathways were differentially regulated in the NBS organoids. Following exposure to bleomycin, NBS organoids exhibited delayed p53-mediated DNA damage response and aberrant trans-synaptic signaling, ultimately leading to neuronal apoptosis. These findings highlight the significance of cerebral organoids as a valuable tool for studying DNA damage-related disorders.