Understanding the role of KDM5B loss-of-function mutations in childhood disorders

Abstract

Developmental disorders (DDs) are a diverse group of chronic conditions that affect the physical, cognitive or behavioural development of a child. The heterogeneous nature of these disorders, and their diverse aetiology poses signifcant diagnostic and therapeutic challenges, where patients are often left with limited treatment options. Increasing evidence highlights the importance of genetic mutations in these disorders. Loss-of-function (LoF) of KDM5B leads to a recognisable disorder characterised by intellectual disability and physical deformities. KDM5B is predominately expressed during early development where it has a crucial role in neurodevelopment. However, despite its association with this disorder, its underlying mechanisms remain under-explored.
This thesis aimed to elucidate the role of KDM5B in early neuronal differentiation, hypothesizing that KDM5B loss-of-function disrupts neuronal differentiation and contributes to pathogenesis of the neurodevelopmental disorder. CRISPR-Cas9 mediated KDM5B knockout models were generated in human neuroblastoma SH-SY5Y cells and induced pluripotent stem cells (iPSCs) to simulate key stages of neuronal development. It was observed that KDM5B LoF delayed the transition from pluripotent stem cell to neural progenitor cell. Conversely, at later stages of differentiation, KDM5B-KO cells exhibited enhanced neurite outgrowth and branching, suggesting a stage-dependent role of KDM5B. Transcriptomic and proteomic analyses further highlighted KDM5B’s involvement in proliferation, RNA splicing regulation, mitochondrial function and cell adhesion.
These fndings increase our understanding of KDM5B’s essential functions in neurodevelopment and have implications for both KDM5B-associated developmental disorders and cancer biology. Future research into these pathways may uncover novel therapeutic targets and further elucidate the diverse roles of KDM5B in human development.

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Identifiers

ORCID for Zoë Walters: orcid.org/0000-0002-1835-5868

ORCID for Sandrine Willaime-Morawek: orcid.org/0000-0002-1121-6419

ORCID for Jane Gibson: orcid.org/0000-0002-0973-8285

ORCID for Gabrielle Wheway: orcid.org/0000-0002-0494-0783

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