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Vol. LXIII, No. 6
March 18, 2011
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Genetic Discoveries Challenge Theories About Stuttering and The King’s Speech
Dr. Changsoo Kang (l) and Dr. Dennis Drayna of NIDCD have been on the hunt for genetic causes of stuttering for years.

Dr. Changsoo Kang (l) and Dr. Dennis Drayna of NIDCD have been on the hunt for genetic causes of stuttering for years.

The King’s Speech, a stirring tribute to the perseverance of King George VI of England and his struggle to conquer his stutter and lead his people through the dark years of World War II, swept the Oscars this year. In King George’s time, stuttering was thought to be the result of emotional trauma in childhood or an unhealthy attachment to a parent, usually the mother. Even today, in regards to the 3 million people who stutter in America (and another 60 million worldwide), there are still some who mistakenly think the disability is caused by psychological problems or nervousness.

But that may begin to change as the result of a recent discovery by a team of NIDCD researchers who have identified three different gene mutations that are responsible for stuttering in some adults. Just like King George’s struggle with his stammer, the search for these genes is a tale of perseverance—as well as an. ability to find things in unexpected places.

The story begins in 2001 in Dr. Dennis Drayna’s laboratory at NIDCD when he began gathering DNA and other data from a cluster of families in Pakistan with a high incidence of stuttering. Pakistan is a good place to study genetic diseases because there is a high rate of intermarriage within extended families. This narrows the gene pool and makes mutations easier to find using genetic linkage studies.

In 2005, Drayna turned up a promising candidate region on chromosome 12 that was likely to harbor a mutant gene, but further progress was proving difficult. When Dr. Changsoo Kang, a visiting fellow from Korea, arrived in Drayna’s lab to help with the study, 87 candidate genes on chromosome 12 had been identified and needed to be sequenced and analyzed to see if anything interesting would turn up.

Forty-five genes and 3 years later, with nothing to show for his efforts, Kang felt tired and frustrated. “I wanted to give up,” he said. “I told Dennis I was ready to go back to Korea.”

For the next week, Kang didn’t do any experiments. He poked through his papers at his desk until one day he picked up his lab notebook, flipped through the pages and noticed something.

It was a mutation in a gene he’d seen before, but hadn’t thought much of. The gene, GNPTAB, was related to a group of diseases known as the mucolipidoses—metabolic disorders so lethal that most babies diagnosed with them die in early childhood. He doubted a gene for a metabolic disorder could have anything to do with stuttering, but he was curious. He began to look through the scientific literature and found a few references to children with milder forms of the muculipidoses who had delayed speech development. But there was nothing that specifically addressed speech problems.

So he did what we all do when we need to know something right away—he Googled. “Mucolipodosis + speech” turned up a web site that described a type of mucolipidosis in which children don’t speak at all. He sensed he was headed in the right direction.

Further sequencing of the DNA from the Pakistani families showed that the mutation was present in some people who stuttered and it was also found in members of some of the original families used in the linkage study. Since the GNPTAB gene was known to work with two other genes—GNPTG and NAGPA— he sequenced those genes as well and found mutations that were present in people who stutter and their families, but not in the control groups. In fact, no one had ever found a human with any disease associated with mutations in NAGPA, until now. Its only known effect is stuttering.

Currently, Kang, Drayna and their team are working with a knock-in mouse model of one of the genetic variants to test their theory that this form of stuttering is the result of a group of cells in the brain dedicated to fluent speech production. Their hypothesis is that such cells are uniquely sensitive to the slight metabolic defect caused by the mutation.

One goal is to use these mice to discover where in the brain this gene is turned on, since this could indicate the location of the cells. Another long-term goal is to see if the human stuttering mutation can disrupt vocal communication in the mouse. However, before the scientists can understand what a stuttering mouse might sound like, they will have to better understand normal mouse speech patterns.

The researchers are looking forward to a future when stuttering can be treated as a biological disorder with a medical cure, instead of looking at it as a character weakness—as in King George’s time—that can’t be helped. NIHRecord Icon


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