|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.
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
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
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.