A defect in intracellular trafficking, the process that cells use to move proteins to their correct locations, causes an inherited form of persistent stuttering, according to a new study led by scientists at the National Institute on Deafness and Other Communication Disorders (NIDCD), part of the National Institutes of Health. The findings extend previous studies, providing new insights into the molecular underpinnings of the disorder and reinforcing the notion that persistent stuttering is a neurological (brain) disorder. The results may contribute to a foundation for the development of new diagnostic and therapeutic approaches for stuttering. The study was published November 5 in the American Journal of Human Genetics.
Stuttering is a speech disorder in which a person repeats or prolongs sounds, syllables, or words, disrupting the normal flow of speech. The disorder affects people of all ages and begins most frequently in young children between the ages of 2 and 6, as they are developing their language skills. Most children outgrow stuttering but many do not. Researchers estimate that as many as 1 percent of Americans, roughly 3 million people, live with persistent stuttering. While the exact causes of stuttering are unknown, scientists believe that it stems from problems with the circuits in the brain that control speech.
Stuttering tends to run in families, and researchers estimate that the contribution of genetic factors to stuttering range as high as 80 percent. In 2010, a team led by Dennis Drayna, Ph.D., chief of the Section on Systems Biology of Communication Disorders in the Laboratory of Molecular Genetics at the NIDCD, for the first time linked three related genes to stuttering. All three genes are involved in intracellular trafficking; in particular, they direct proteins to a compartment where they are broken down and their components recycled.
While the discovery of the previously identified genes represented an important breakthrough, the researchers estimated that together, those genes only accounted for 8 to 16 percent of cases of inherited stuttering in the United States and elsewhere. Researchers have continued to seek additional contributing genetic factors.
In the current study, Drayna's team set out to identify other genes involved in stuttering by focusing on a large family from Cameroon, West Africa, that had many cases of stuttering. The researchers identified mutations in a gene called AP4E1 that are present in individuals in this family who stutter but that did not exist anywhere else in the world, except in two other Cameroonians who were unrelated to this family and who stutter. Other mutations in this gene were subsequently found in individuals who stutter from Brazil, the United States, England, Pakistan, and Cameroon.
Like the stuttering genes Drayna's team discovered earlier, AP4E1, which is a component of a four-part complex, plays a role in intracellular trafficking. Using biochemical methods, the scientists found that the AP4E1 complex physically interacts with one of the previously identified stuttering-associated proteins, suggesting that they work together closely to steer proteins to their proper cellular destinations.
As part of the study, researchers also looked for the AP4E1 mutations in unrelated individuals from Cameroon, Pakistan, and North America who stuttered and those who did not. The researchers found a higher frequency of AP4E1 variants among individuals from Pakistan and Cameroon who stuttered, compared to those who did not. Differences in the variant frequency among two North American groups did not show a significant difference, however. Based on their finding, the researchers estimated that 2.1 to 3.7 percent of cases of persistent stuttering are caused by mutations in AP4E1.
Together with Drayna's earlier work, these findings strongly implicate intracellular trafficking, especially the process of directing proteins to the cell's recycling compartment, in persistent stuttering. Defects in intracellular trafficking have been linked to other neurological disorders, such as amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Alzheimer's disease, suggesting that certain nerve cell pathways are particularly sensitive to impairment of this process. Their findings do not indicate, however, that persistent stuttering is an early indicator of these other, more common disorders.
"I think one of the most important aspects of our work is that it shows that stuttering, at its source, is a biological problem," said Drayna. "In the future, we may be able to build on what we've learned about the genetics of stuttering to develop novel diagnostics and therapies."
This work was supported by NIDCD intramural research funds (Z1A-DC000046 and Z1A-DC000039) and by intramural funds from the Eunice Kennedy Shriver National Institute on Child Health and Human Development (Z1A-HD001607). The Stuttering Foundation of America, the Hollins Communications Research Institute, and the National Stuttering Association also contributed to the study.