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Reversal of proliferation deficits caused by chromosome 16p13.11 microduplication through targeting NFκB signaling: an integrated study of patient-derived neuronal precursor cells, cerebral organoids and in vivo brain imaging.

ABSTRACT: The molecular basis of how chromosome 16p13.11 microduplication leads to major psychiatric disorders is unknown. Here we have undertaken brain imaging of patients carrying microduplications in chromosome 16p13.11 and unaffected family controls, in parallel with iPS cell-derived cerebral organoid studies of the same patients. Patient MRI revealed reduced cortical volume, and corresponding iPSC studies showed neural precursor cell (NPC) proliferation abnormalities and reduced organoid size, with the NPCs therein displaying altered planes of cell division. Transcriptomic analyses of NPCs uncovered a deficit in the NFκB p65 pathway, confirmed by proteomics. Moreover, both pharmacological and genetic correction of this deficit rescued the proliferation abnormality. Thus, chromosome 16p13.11 microduplication disturbs the normal programme of NPC proliferation to reduce cortical thickness due to a correctable deficit in the NFκB signalling pathway. This is the first study demonstrating a biologically relevant, potentially ameliorable, signalling pathway underlying chromosome 16p13.11 microduplication syndrome in patient-derived neuronal precursor cells.

SUBMITTER: Johnstone M

PROVIDER: S-EPMC6344377 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background16p13.11 microduplication syndrome has a variable presentation and is characterized primarily by neurodevelopmental and physical phenotypes resulting from copy number variation at chromosome 16p13.11. Given its variability, there may be features that have not yet been reported. The goal of this study was to use a patient "self-phenotyping" survey to collect data directly from patients to further characterize the phenotypes of 16p13.11 microduplication syndrome.ObjectiveThis study aimed to (1) discover self-identified phenotypes in 16p13.11 microduplication syndrome that have been underrepresented in the scientific literature and (2) demonstrate that self-phenotyping tools are valuable sources of data for the medical and scientific communities.MethodsAs part of a large study to compare and evaluate patient self-phenotyping surveys, an online survey tool, Phenotypr, was developed for patients with rare disorders to self-report phenotypes. Participants with 16p13.11 microduplication syndrome were recruited through the Boston Children's Hospital 16p13.11 Registry. Either the caregiver, parent, or legal guardian of an affected child or the affected person (if aged 18 years or above) completed the survey. Results were securely transferred to a Research Electronic Data Capture database and aggregated for analysis.ResultsA total of 19 participants enrolled in the study. Notably, among the 19 participants, aggression and anxiety were mentioned by 3 (16%) and 4 (21%) participants, respectively, which is an increase over the numbers in previously published literature. Additionally, among the 19 participants, 3 (16%) had asthma and 2 (11%) had other immunological disorders, both of which have not been previously described in the syndrome.ConclusionsSeveral phenotypes might be underrepresented in the previous 16p13.11 microduplication literature, and new possible phenotypes have been identified. Whenever possible, patients should continue to be referenced as a source of complete phenotyping data on their condition. Self-phenotyping may lead to a better understanding of the prevalence of phenotypes in genetic disorders and may identify previously unreported phenotypes.

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Reversal of proliferation deficits caused by chromosome 16p13.11 microduplication through targeting NFκB signaling: an integrated study of patient-derived neuronal precursor cells, cerebral organoids and in vivo brain imaging.

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