Navigation Links
Surprising pathway implicated in stuttering
Date:11/22/2011

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.


'/>"/>

Contact: Judy Martin
martinju@wustl.edu
314-750-4213
Washington University School of Medicine
Source:Eurekalert

Related medicine news :

1. Cosmetic Surgery Error in New York Strikes Medical Malpractice Lawyers as Unsurprising
2. Stanford/Packard study finds surprising disparity in where chronically ill kids hospitalized
3. Anger Spurs Surprising Changes in the Body
4. Surprising find may yield new avenue of treatment for painful herniated discs
5. Pancreatic Cancer Surprisingly Slow to Arise: Study
6. Study finds surprising gender differences related to sexual harassment
7. Surprising finding from smoke inhalation study
8. Surprising drop in physicians willingness to accept patients with insurance
9. Neuroscientists find famous optical illusion surprisingly potent
10. The Generation X Report: U-M survey paints a surprisingly positive portrait
11. Molecular pathways linked to sex, age affect outcomes in lung cancer
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:4/26/2017)... ... April 26, 2017 , ... Infertility may be a result ... has helped many women become pregnant upon treating their diagnosis. , ... outpatient evaluations. We can provide the necessary information to diagnose and treat ...
(Date:4/26/2017)... Doylestown, Pa. (PRWEB) , ... ... ... Solutions division, which provides an agile ecosystem and domain expertise for sponsors ... end-to-end, configurable randomization and trial supply management (RTSM) software platform. Bioclinica ...
(Date:4/25/2017)... , ... April 25, 2017 ... ... in Newport Beach, California, committed to raising awareness for Duchenne muscular dystrophy, ... from its randomized CAP-1002 (cardiosphere-derived cells) Phase I/II HOPE clinical trial in ...
(Date:4/25/2017)... ... 2017 , ... Lake Park Dental is now accepting new patients with crooked ... FL. With the help of this highly-effective, yet convenient system, patients can straighten their ... and less pain. , Drs. Sarah Jockin, Nicole Morganti, Sara Spear and Elizabeth ...
(Date:4/25/2017)... ... April 25, 2017 , ... Buyers and sellers in the thriving ... and head shops –can’t help but be heartened by the industry’s current surge. But ... aptly described as “skunk smell.” At last they can simply, safely and effectively ...
Breaking Medicine News(10 mins):
(Date:4/19/2017)... April 19, 2017 The Mobile X-Ray product segment ... healthy CAGR during the forecast period Mobile X-Ray ... global digital mobile X-Ray devices market, which is estimated to ... expanding at a CAGR of 7% over the forecast period. ... of more than US$ 100 Mn in 2017 over 2016. ...
(Date:4/19/2017)... Global Prostate Cancer Therapeutics Market: Overview ... cancer therapeutics market analyzes the current and future ... prostate cancer, launch of promising emerging therapies, as ... drugs & therapeutic biological products, and high growth ... side effects are some of the drivers expected ...
(Date:4/19/2017)...  Sorrento Therapeutics, Inc. (NASDAQ: SRNE ... new treatments for cancer and other unmet medical ... announced underwritten public offering of 23,625,084 shares of ... of $2.00 per share, before deducting underwriting discounts ... Sorrento.  The net proceeds to Sorrento from this ...
Breaking Medicine Technology: