Featured Research

from universities, journals, and other organizations

Surprising pathway implicated in stuttering

Date:
November 23, 2011
Source:
Washington University School of Medicine
Summary:
Researchers 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.

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."

The research is available online in the Journal of Biological Chemistry

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. 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.

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.


Story Source:

The above story is based on materials provided by Washington University School of Medicine. The original article was written by Julia Evangelou Strait. Note: Materials may be edited for content and length.


Journal References:

  1. W.-S. Lee, C. Kang, D. Drayna, S. Kornfeld. Analysis of Mannose 6-Phosphate Uncovering Enzyme Mutations Associated with Persistent Stuttering. Journal of Biological Chemistry, 2011; 286 (46): 39786 DOI: 10.1074/jbc.M111.295899
  2. Changsoo Kang, Sheikh Riazuddin, Jennifer Mundorff, Donna Krasnewich, Penelope Friedman, James C. Mullikin, Dennis Drayna. Mutations in the Lysosomal Enzyme–Targeting Pathway and Persistent Stuttering. New England Journal of Medicine, 2010; 362 (8): 677 DOI: 10.1056/NEJMoa0902630

Cite This Page:

Washington University School of Medicine. "Surprising pathway implicated in stuttering." ScienceDaily. ScienceDaily, 23 November 2011. <www.sciencedaily.com/releases/2011/11/111122162834.htm>.
Washington University School of Medicine. (2011, November 23). Surprising pathway implicated in stuttering. ScienceDaily. Retrieved September 16, 2014 from www.sciencedaily.com/releases/2011/11/111122162834.htm
Washington University School of Medicine. "Surprising pathway implicated in stuttering." ScienceDaily. www.sciencedaily.com/releases/2011/11/111122162834.htm (accessed September 16, 2014).

Share This



More Health & Medicine News

Tuesday, September 16, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

EU Ministers and Experts Meet to Discuss Ebola Reponse

EU Ministers and Experts Meet to Discuss Ebola Reponse

AFP (Sep. 15, 2014) The European Commission met on Monday to coordinate aid that the EU can offer to African countries affected by the Ebola outbreak. Duration: 00:58 Video provided by AFP
Powered by NewsLook.com
Despite The Risks, Antibiotics Still Overprescribed For Kids

Despite The Risks, Antibiotics Still Overprescribed For Kids

Newsy (Sep. 15, 2014) A new study finds children are prescribed antibiotics twice as often as is necessary. Video provided by Newsy
Powered by NewsLook.com
FDA Eyes Skin Shocks Used at Mass. School

FDA Eyes Skin Shocks Used at Mass. School

AP (Sep. 15, 2014) The FDA is considering whether to ban devices used by the Judge Rotenberg Educational Center in Canton, Massachusetts, the only place in the country known to use electrical skin shocks as aversive conditioning for aggressive patients. (Sept. 15) Video provided by AP
Powered by NewsLook.com
Respiratory Virus Spreads To Northeast, Now In 21 States

Respiratory Virus Spreads To Northeast, Now In 21 States

Newsy (Sep. 14, 2014) The respiratory virus Enterovirus D68, which targets children, has spread from the Midwest to 21 states. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins