Intern Sanford Burnham Prebys Medical Discovery Institute, California, United States
Abstract: Kabuki Syndrome (KS) is an orphan disease caused by a genetic disorder that leads to abnormal growth & development affecting 1 in every 32,000 new births. It is often characterized by facial features that resemble traditional Japanese Kabuki theater masks. KS can lead to craniofacial abnormalities, hearing loss, problems with vision, congenital heart defects, feeding difficulties, immune dysfunction, poor growth, skeletal & dermatoglyphic abnormalities, and difficulties with cognition and/or development. There are two known genetic mutations that result in KS and they are considered sporadic. Type 1 is a result of a genetic mutation on the KMT2D gene located on chromosome 12. This gene is responsible for providing instructions for making an enzyme that modifies histone H3K4. This genetic mutation is known in approximately 75% of KS patients. The second less common mutation is the KMD6A mutant, which is found on the X chromosome. KMD6A is a histone demethylase which plays a crucial role in gene regulation during development. The KMD6A mutant has only been found in 144 individuals around the world as of 2024. Due to the high mortality rate and rarity of the disease, there are limitations on the ability to study KS with physiologically relevant models resulting in a lack of cure or established therapy for KS. Importantly, insights into understanding and treating KS can provide guides for treating other diseases whose etiology rests on abnormal epigenetic regulation. With parental consent, we obtained discarded skin fibroblasts from a Type 1 KS baby undergoing gastrostomy tube placement to generate induced pluripotent stem cells (iPSCs). We accomplished this using standard Yamanaka factors delivered via Sendai Virus. When validation is completed by performing ICC for SC markers and Embryoid Body formation, we will use these hiPSCs, differentiated into an array of neural cells, to create 2D and 3D models of the human brain. By validating and optimizing the lab’s established protocols for generating cortical interneurons (CINs) and cerebral organoids (CODs), we aim to provide a model that might shed light on the physiological, compositional, or circuitry deficiencies in KS and provide a model for identifying or designing therapies that can target and preempt these problems in utero, potentially improving quality of life.
