Surprising pathway implicated in stuttering

November 22, 2011, Washington University School of Medicine

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 affecting cellular recycling centers called lysosomes actually play a role in causing some people to .

"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."

The research is available online in the .

Genetic clues to stuttering were first identified in a paper published in the 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 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 . Drayna's work identified three separate mutations in NAGPA in individuals who stutter. And according to Lee's biochemical analysis, all three of the mutations impaired the enzyme, but each did so in a different way. In general, mutations in a gene often cause the resulting protein to be folded into the wrong shape. Cells are very good at recognizing misfolded proteins and destroying them.

In this case, Lee's biochemical analysis shows that two mutations appear to trap the proteins in the cell's protein manufacturing center, though some get out before being destroyed.

"It's not an all-or-nothing thing," Kornfeld says. "Of the material that does get out, its activity is normal."

But the third mutation causes a larger folding problem and the protein is destroyed just minutes after being made.

Such findings offer a glimpse at possible future therapies for stuttering. For two of the mutations at least, the problem is not that the protein can't function, but rather that it can't get out of the cell's protein manufacturing center and go to the intracellular site where it acts to direct proteins to lysosomes. If some compound can be found that helps the protein escape, Lee's work suggests that it would function normally. But Kornfeld cautions that this type of therapy for stuttering is a long way off.

"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.

Explore further: Persistence of stuttering into teenage years predicted by simple model

More information: Lee WS, Kang C, Drayna D, Kornfeld S. Analysis of mannose 6-phosphate uncovering enzyme mutations associated with persistent stuttering. Journal of Biological Chemistry. Nov. 18, 2011.

Related Stories

Persistence of stuttering into teenage years predicted by simple model

April 18, 2011
Wellcome Trust researchers have developed a model that can correctly predict whether a child will recover from a stutter in four out of five cases. The model should allow clinicians to target interventions at those children ...

Profound reorganization in brains of adults who stutter

August 15, 2011
Hearing Beethoven while reciting Shakespeare can suppress even a King's stutter, as recently illustrated in the movie "The King's Speech". This dramatic but short-lived effect of hiding the sound of one's own speech indicates ...

Recommended for you

Peers' genes may help friends stay in school, new study finds

January 18, 2018
While there's scientific evidence to suggest that your genes have something to do with how far you'll go in school, new research by a team from Stanford and elsewhere says the DNA of your classmates also plays a role.

Two new breast cancer genes emerge from Lynch syndrome gene study

January 18, 2018
Researchers at Columbia University Irving Medical Center and NewYork-Presbyterian have identified two new breast cancer genes. Having one of the genes—MSH6 and PMS2—approximately doubles a woman's risk of developing breast ...

A centuries-old math equation used to solve a modern-day genetics challenge

January 18, 2018
Researchers developed a new mathematical tool to validate and improve methods used by medical professionals to interpret results from clinical genetic tests. The work was published this month in Genetics in Medicine.

Can mice really mirror humans when it comes to cancer?

January 18, 2018
A new Michigan State University study is helping to answer a pressing question among scientists of just how close mice are to people when it comes to researching cancer.

Epigenetics study helps focus search for autism risk factors

January 16, 2018
Scientists have long tried to pin down the causes of autism spectrum disorder. Recent studies have expanded the search for genetic links from identifying genes toward epigenetics, the study of factors that control gene expression ...

Group recreates DNA of man who died in 1827 despite having no body to work with

January 16, 2018
An international team of researchers led by a group with deCODE Genetics, a biopharmaceutical company in Iceland, has partly recreated the DNA of a man who died in 1827, despite having no body to take tissue samples from. ...

2 comments

Adjust slider to filter visible comments by rank

Display comments: newest first

Telekinetic
not rated yet Nov 22, 2011
Talkin' 'bout my g-g-g-genetic mutation...
photon209
not rated yet Nov 23, 2011
I wonder if this points to a connection between Sarcoidosis and stuttering - from a connection of lysosomes and the granuoles associated with Sarcoid. I've had both for many years.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.