Rebecca Muhle, MD, PhD

Dr. Muhle works with members of Dr. James Noonan's lab to understand how genetic changes in people can lead to autism spectrum disorder (ASD) and other neurodevelopmental disorders. Changes in DNA that disrupt the production or function of proteins are referred to as “loss-of-function” mutations. A loss-of-function mutation in a gene critical for brain development may disrupt the expression or function of that gene’s protein in the brain, resulting in atypical neurodevelopment and an increased risk for neurodevelopmental disorders such as ASD in people that carry them.

People that carry a loss-of-function mutation in genes critical for brain development may have disrupted expression or function of that gene in the brain, resulting in atypical patterns of neurodevelopment and an increased risk for ASD. One such gene is CHD8. It produces a protein (CHD8) that binds to the regulatory region of other genes and thereby controls the expression of these genes, many of which are genes that are also disrupted in people with ASD. Genes targeted by CHD8 are also part of a network of genes that are active during a critical period of fetal brain development.

The specific molecular function and role of CHD8 in specific cell types in the developing brain is largely unknown and discovering its role in brain development is a major focus of the lab. The lab has generated several model systems in animals and human cell lines to explore the normal function of CHD8 in specific cells of the developing cortex. They utilize high-throughput sequencing to determine the gene targets of CHD8 in specific cell types and their gene expression profiles. By determining the list of genes that are targeted by CHD8 or are altered by CHD8 loss-of-function in specific types of brain cells, they can assess whether there is a predominance of other genes that also contribute to ASD risk. They interpret this as an indicator that those cell types are important players in the development of autism. By exploring the functions of these genes and learning what kinds of biological pathways connect these genes with each other, this can increase the knowledge of the mechanisms underlying autism and gain new insights into the origins of the condition.