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A single mutation in a seemingly unrelated gene causes speech problems for humans and mice alike.

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‘Stuttering’ mice may help unravel mystery of human speech disorder

Mice supposedly don't speak, so they can't stutter. But by tinkering with a gene that appears to be involved in human speech, researchers have created transgenic mice whose pups produce altered vocalizations in a way that is similar to stuttering in humans. The mice could make a good model for understanding stuttering; they could also shed more light on how mutations in the gene, called Gnptab, cause the speech disorder.

Stuttering is one of the most common speech disorders in the world, affecting nearly one out of 100 adults in the United States. But the cause of the stammering, fragmented speech patterns remains unclear. Several years ago, researchers discovered that stutterers often have mutations in a gene called Gnptab. Like a dispatcher directing garbage trucks, Gnptab encodes a protein that helps to direct enzymes into the lysosome—a compartment in animal cells that breaks down waste and recycles old cellular machinery. Mutations to other genes in this system are known to lead to the buildup of cellular waste products and often result in debilitating diseases, such as Tay-Sachs. How mutations in Gnptab causes stuttered speech remains a mystery, however.

To get to the bottom of things, neuroscientist Terra Barnes and her team at Washington University in St. Louis in Missouri produced mice with mutation in the Gnptab gene and studied whether it affected the ultrasonic vocalizations that newly born mouse pups emit when separated from their mothers. Determining whether a mouse is stuttering is no easy task; as Barnes points out, it can even be difficult to tell whether people are stuttering if they’re speaking a foreign language. So the team designed a computer program that listens for stuttering vocalization patterns independent of language. The program listens to the number of vocalizations per minute and the length of pauses during bouts of vocalization. In humans, it can distinguish a person who stutters from a control subject 79% of the time.

The program showed that mice with mutant copies of the Gnptab gene had less frequent vocalizations and more long pauses than normal mice. However, the afflicted mice produced all of the same sounds in the same proportion as their wild-type siblings, indicating they were still physically capable of normal vocalizations. And an array of cognitive and physical challenges showed that the stuttering mice were otherwise healthy. That suggests that despite the vast differences in complexity between human and mouse vocalizations, mutated copies of Gnptab have similar effects, the researchers write today in Current Biology, which makes the mouse a potentially valuable model for studying stuttering. “We can throw every drug in the book at it," Barnes says. "We can try to figure out which part of the brain is affected.”

“I think it’s further support that the genes in this pathway do have something to do with speech,” says Stuart Kornfeld, a cell biologist at the Washington University School of Medicine in St. Louis, who was not involved in the study.

But how a single mutation in a common cellular housekeeping gene can result in stuttered speech remains unknown. One possibility is that the neurons involved in speech are particularly sensitive to the waste accumulation caused by missing lysosomal enzymes, Kornfeld says. But there's no evidence for this yet, he adds; in fact, scientists don't exactly know which neurons are involved in speech.

The buildup of undigested waste products from a malfunctioning lysosome system is just one possible cause, says Tim Holy at the Washington University School of Medicine in St. Louis, Missouri, one of the paper’s co-authors. “Another possibility is that these genes have another function that has not yet been recorded in any other context.”