Project 458834

Kabuki Syndrome is a rare genetic disease that affects 1 in 40,000 individuals and is characterized by intellectual disability, abnormal development of the brain and heart, and malformations of the face and skull. Genetic diseases involve errors in patients' DNA. In Kabuki Syndrome, these errors can occur in a specific DNA segment that codes for the KDM6A protein. This protein modifies complexes around which DNA is wrapped, called histones. By modifying histones, KDM6A can signal to the cell to turn on the expression of certain genes. My preliminary results in stem cell models show that when KDM6A is lost, genes involved in making neural cells are reduced. This proposed research thus aims to understand the molecular mechanism that involves KDM6A, KDM6A-associated histone modifications, and certain genes required for making neural cells in order to understand why KDM6A causes Kabuki Syndrome. We will be using genetically engineered stem cells and stem cells derived from Kabuki Syndrome patients' blood samples to investigate our question. We expect to see an increase in a specific kind of histone modification when KDM6A is lost, which could lead to a decrease of neural genes that are normally controlled by KDM6A-associated histone modifications. By uncovering the molecular mechanism underlying KDM6A-caused Kabuki Syndrome, we hope to help clinicians better understand a subgroup of patients who present with developmental abnormalities, and to open doors to the development of potential treatments for this disorder.