Surprising pathway implicated in stuttering
Baku, January 6 (AZERTAC). Researchers at Washington University School of Medicine in St. Louis have obtained new evidence that at least some persistent stuttering is caused by mutations in a gene governing not speech, but a metabolic pathway involved in recycling old cell parts. Beyond a simple association, the study provides the first evidence that mutations affecting cellular recycling centers called lysosomes actually play a role in causing some people to stutter. "This was extremely unexpected," says senior author Stuart A. Kornfeld, MD, the David C. and Betty Farrell Professor of Medicine. "Why would impairment in a lysosomal pathway lead to stuttering? We don`t know the answer to that. Partly because we don`t know very much about the mechanisms of speech, including which neurons in the brain are involved. So we can`t fully explain stuttering, but now we have clues." Genetic clues to stuttering were first identified in a paper published in the New England Journal of Medicine in February 2010. In it, Dennis Drayna, PhD, a senior investigator with the National Institute on Deafness and Other Communication Disorders and a co-author on the current study, and his colleagues reported results of genetic studies on members of a large Pakistani family, many of whom stutter. Among most of the stuttering family members, they found mutations in three genes involved in directing proteins to the lysosome. These same mutations were present in many unrelated individuals in Pakistan, North America and Europe who stutter, but not in those with normal speech. "They found mutations in three genes that encode a pathway for directing newly made lysosomal enzymes to the lysosomes," Kornfeld says. "And it turned out to be a pathway we discovered years ago. So this is a nice collaboration." Until now, one of the three genes, NAGPA, had not been implicated in any human disorder. This is where Kornfeld and Wang-Sik Lee, PhD, research instructor in medicine at Washington University, began their in-depth biochemical investigation of the mutations that Drayna`s group identified. NAGPA encodes an enzyme responsible for the last step in "addressing" proteins to the lysosome. Drayna`s work identified three separate mutations in NAGPA in individuals who stutter. "There are billions of neurons in the brain, and we have very little idea which neurons are involved in speech," he says. "Our main finding is that these three mutations in NAGPA in people with persistent stuttering all have harmful effects. This is biochemical evidence that these mutations are meaningful, and not just markers of some other genetic change that is the real cause." Having described the three harmful mutations in NAGPA, Kornfeld`s group is now performing biochemical analyses on the other two mutated genes Drayna`s group identified: GNPTAB and GNPTG. Drayna and his colleagues estimate that these three mutated genes account for only about 10 percent of people who stutter with a family history. As such, they are continuing the search for additional genes responsible for stuttering. This work was supported by grants from the National Institutes of Health (NIH) and from the National Institute on Deafness and Other Communication Disorders, which is a part of the NIH.
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