Section on Genetics of Communication Disorders

Dennis Drayna, Ph.D., Scientist Emeritus

Research Statement

In the Section on Genetics of Communication Disorders (Laboratory of Communication Disorders), we used family- and population-based genetic methods to identify genes responsible for human communication disorders. The lab had a major focus on the speech disorder stuttering, for which we identified causative mutations in several genes. We studied the biochemical and cellular effects of these mutations, and we used mouse model systems to study the effects of these mutations on mouse ultrasonic vocalizations. The long-term goal of our work was to identify specific neuronal pathologies caused by these mutations.

We also performed studies on the sense of taste, where our overall goal was understanding how naturally occurring genetic variation contributes to differences in the sense of taste in humans. We focused on a study of variation in taste perception genes and tobacco use, with a particular interest in menthol tobacco use and variation in the TRPM8 gene, which encodes the menthol receptor.

Accomplishments

Stuttering: We studied families in which many individuals stutter. Genetic linkage studies can identify the location of the gene or genes responsible for stuttering in these families. We enrolled a large group of families in Pakistan, where marriages between cousins are common. Each of these families has multiple cases of stuttering, and our genetic linkage studies identified major linkage signals, indicating different causative genes, on chromosomes 12, 3, and 16.

We also identified a large, English-speaking family in Cameroon, West Africa, in which stuttering occurs in more than 40 family members. Linkage studies in this family have shown that stuttering is due to several different genes, each acting in a different branch of the family. These genes are located on chromosome 2, 3, 14, and 15. Studies of stuttering families from Brazil identified yet another locus, on chromosome 10, that carries a stuttering gene in this population.

Studies of the chromosome 12 locus identified causative mutations in the gene GNPTAB, and additional studies identified causative mutations in the related GNPTG and NAGPA genes. Together these three genes appear to account for up to 15 percent of stuttering cases in the U.S., as well as elsewhere in the world. Studies of the chromosome 15 locus in the Cameroonian family identified mutations in the AP4E1 gene, which encodes part of a complex involved in trafficking components within cells. Additional studies demonstrated that the product of the NAGPA gene interacts with the AP4 complex, and thus all of the stuttering genes identified to date revealed deficits in the mechanism cells use to move components to their proper location within the cell. Mutations in AP4E1 appear to account for up to 5 percent of stuttering cases in worldwide populations.

We engineered mouse lines that carry mutations that cause stuttering in humans. Like the humans who carry these mutations, these mice are normal in all ways measured to date, except that they display subtle differences in their ultrasonic vocalizations. We used these mouse lines to attempt to identify the cells within the brain that mediate this abnormal vocalization.

Taste perception: Our studies focused on taste perception and tobacco use, particularly flavored tobacco use. We studied variants in genes encoding components of the human taste perception machinery, including genes encoding taste receptors, to evaluate the hypothesis that such genetic variation is associated with mentholated tobacco use, or with tobacco use in general. Menthol tobacco use displays wide divergence among different ethnic groups in the United States, and we sought to determine whether the strong ethnic differences could be accounted for by genetically encoded differences in taste perception.