Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Surprising pathway implicated in stuttering

23.11.2011
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.


Kornfeld
“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.

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.

Kang C, Riazuddin S, Mundorff J, Krasnewich D, Friedman P, Mullikin JC, Drayna D. Mutations in the lysosomal enzyme-targeting pathway and persistent stuttering. The New England Journal of Medicine. February 2010.

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.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Judy Martin | EurekAlert!
Further information:
http://www.wustl.edu

More articles from Life Sciences:

nachricht Nerves control the body’s bacterial community
26.09.2017 | Christian-Albrechts-Universität zu Kiel

nachricht Ageless ears? Elderly barn owls do not become hard of hearing
26.09.2017 | Carl von Ossietzky-Universität Oldenburg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: The fastest light-driven current source

Controlling electronic current is essential to modern electronics, as data and signals are transferred by streams of electrons which are controlled at high speed. Demands on transmission speeds are also increasing as technology develops. Scientists from the Chair of Laser Physics and the Chair of Applied Physics at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) have succeeded in switching on a current with a desired direction in graphene using a single laser pulse within a femtosecond ¬¬ – a femtosecond corresponds to the millionth part of a billionth of a second. This is more than a thousand times faster compared to the most efficient transistors today.

Graphene is up to the job

Im Focus: LaserTAB: More efficient and precise contacts thanks to human-robot collaboration

At the productronica trade fair in Munich this November, the Fraunhofer Institute for Laser Technology ILT will be presenting Laser-Based Tape-Automated Bonding, LaserTAB for short. The experts from Aachen will be demonstrating how new battery cells and power electronics can be micro-welded more efficiently and precisely than ever before thanks to new optics and robot support.

Fraunhofer ILT from Aachen relies on a clever combination of robotics and a laser scanner with new optics as well as process monitoring, which it has developed...

Im Focus: The pyrenoid is a carbon-fixing liquid droplet

Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.

A warming planet

Im Focus: Highly precise wiring in the Cerebral Cortex

Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.

The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Nerves control the body’s bacterial community

26.09.2017 | Life Sciences

Four elements make 2-D optical platform

26.09.2017 | Physics and Astronomy

Goodbye, login. Hello, heart scan

26.09.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>