In a study recently posted in MedRXive, Dr. Dennis Drayna and colleagues report research findings that support a role for a particular brain cell type called astrocytes in stuttering. The story began more than a decade ago, when their team found evidence for the existence of a gene that caused stuttering in many members of a large Pakistani family. This gene was located on chromosome 3, but the identity of the causative gene at this location proved elusive. With continued research, a subtle mutation in a gene called ZBTB20 was identified, and solid evidence gradually developed that this mutant gene was the cause of stuttering in this family. The gene is called ZBTB20. This gene encodes a so-called transcription factor, and it regulates the expression of other genes. 

Dr. Drayna explained: “All the cells in our body have the same DNA.  So why, for example, is a bone cell so different from a liver cell, or any of the other cell types we have? The answer lies in which of the genes in our DNA are turned on and which are turned off. The process of turning on just the right genes required to make a particular cell type is done by transcription factors. As you might guess, transcription factors are essential for the development of the organs and particular cell types in our bodies.”

In work done by many researchers, ZBTB20 has long been known to control the development of astrocytes, an important cell type in the brain. This was particularly interesting because, In previous work, Dr. Drayna’s group engineered mutations found in human stuttering into mice, and then showed that the mice carrying these mutations displayed alterations in their vocalization that are similar to some features of human stuttering. While these mice were apparently normal in most features, a detailed analysis of the brains of these mice showed marked deficits in astrocytes. 

Dr. Drayna noted: “While this result implicating astrocytes was intriguing and suggestive, it was found in mice. This is only an animal model, and one that has obvious limitations for understanding human speech. Our ZBTB20 findings now provide the first connection in humans between astrocytes and stuttering.”

Mutations in ZBTB20 appear to be a relatively uncommon cause of stuttering.  While such mutations occur much more frequently in individuals who stutter compared to the general population (where they are very rare), they are found in less than 1% of individuals who stutter. With a particular cell type of interest to pursue, it is hoped that further progress can be made in understanding stuttering at a highly detailed level within the brain.

Dr. Drayna received his bachelor’s degree from the University of Wisconsin in 1976, and his Ph.D. from Harvard University in 1981, followed by postdoctoral training at the Howard Hughes Medical Institute at the University of Utah. He joined the NIDCD in 1997, focusing on disorders of auditory pitch perception, variation in human taste perception, and disorders of voice and speech. Dr. Drayna’s work has had a major focus on the genetics and neuroscience of stuttering.

Publication/reference: Frigerio-Domingues, C., Raza, M.H., Han, T.-U., Barnes, T., Shaw, P., Sudre, G., Riazuddin, S., Morell, R., and Drayna D. Mutations in ZBTB20 in individuals with persistent stuttering. MedRXive 2022: https://medrxiv.org/cgi/content/short/2022.11.03.22281471v1 [1]

From the Summer 2023 Magazine