Leveraging human genetics to understand brain development and identify mutations that cause neurological disorders
The genetic mutations that lead to many neurodevelopmental disorders are still unknown. Our laboratory addresses this gap in knowledge using cellular biology and –omics-based approaches. We aim to identify and characterize new mutations to help define disease mechanisms. These efforts will lead to improvements in therapies for catastrophic neurological diseases in children.
Our laboratory uses human genetics to understand the fundamental basis of brain development and diseases that affect brain architecture. Working with clinicians from around the world, we strive to identify the mutations that cause disease and then take a deeper dive into the cellular and molecular biology of those mutations to understand the pathogenesis of disease as well as establishing the building blocks of normal brain development.
Our research efforts center on rare diseases – those that occur at rates of 1 in 100,000 to 1 in 1000000 cases globally – with a specific focus on microcephaly, lissencephaly, and Kabuki syndrome. Advances in molecular genetics have revealed correlations between specific biological processes and these syndromes, allowing triangulation on functional etiology. Despite cutting-edge technological advances like whole exome and whole genome sequencing, the discovery of disease-causing mutations for diseases like these remains relatively underrepresented. We aim to bridge this critical gap between the laboratory and the work of clinicians and geneticists to elucidate the underlying mechanisms of neurological diseases.
A significant focus of our laboratory involves research of the centrosome – the microtubule organizing center of cells and, from a developmental perspective, the origin of most developmental neurological diseases. We aim to understand the centrosome’s role in brain development, a process for us that begins with identifying human mutations, modeling it in CRISPR modified cells and then bringing the fruits of our discoveries to patient samples. Our novel workflow continues in mouse models where we strive to phenocopy the human disorder in vivo for further dissection of disease mechanism.
Specifically, we are interested in asking 1) whether Kabuki syndrome is a disease of disrupted centrosome function, 2) how does centrosome loss disrupt cortical expansion, and 3) how does the centrosome control neuronal migration? Advances in genetic analysis and biological insights stimulated by our work will provide a blueprint for therapeutic intervention.
The methodologies we use in our laboratory involve a melding of cellular biology, high resolution imaging, mouse models and a variety of omics-based approaches that generate large data sets for analysis. We then interlace our findings from such large data sets with known human mutations, creating a priority list of potential genetic mutations for further investigation.
Dr. Kodani earned his BA in Molecular and Cell Biology from the University of California, Berkeley, and his PhD in Development and Cell Biology from the University of California, Irvine. He completed his postdoctoral training in the laboratory of Jeremy Reiter, MD, PhD, at the University of California, San Francisco, before launching his independent career in the Department of Genetics and Genomics at Boston Children’s Hospital. Having joined St. Jude in 2020, Dr. Kodani continues his groundbreaking and renowned research on the impact of human mutations on brain development. He works with clinicians around the world to identify mutations that give rise to some of the rarest diseases in order to better understand them and ultimately develop better therapeutic approaches.
Energetic and collegial team, driven by creativity and scientific curiosity, committed to the mission of finding cures and saving children.