(MRC CASE) Developing robust brain organoids to understand intellectual disability in Kabuki syndrome

About the Project

Kabuki Syndrome (KS1) is a neurodevelopmental disorder caused by loss-of-function genetic variants in KMT2D, which encodes a histone 3 lysine methyltransferase. It causes intellectual disability, post-natal growth retardation and craniofacial dysmorphology. The mechanisms underlying neurodevelopmental dysfunction in KS1 is not fully understood and is under experimental analysis in our labs. Using human pluripotent stem cells generated from individuals with KMT2D mutations and appropriate control lines, we developed 2D developmental protocols to generate cortical neurons. We found epigenetic and transcriptomic changes between control and mutant lines with disease causing mutations across three stages of differentiation (Cuvertino et al 2025). However, the brain is a 3-dimensional organ with considerable complexity- just considering the cortex. Therefore, in this project we will refine our new 3D brain cortical organoid model, extending development to more mature stages. The student will combine transcriptomics, epigenomics and different modes of cell imaging to gain a detailed analysis of when critical changes occur in KS1 brain development, what the major changes are and which cells they affect. With the valuable input of our Case partner Bio-techne, we will be able to refine the information we obtain from organoids including identifying lineage and stage specific changes in organelle behaviour. Supported by already funded research identifying drug targets, ultimately this understanding will take us nearer to new targeted treatments for KS1 patients to relieve symptoms and one day fully alleviate disease.