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If you’ve seen The King’s Speech, you know that stuttering (a.k.a. stammering) is a debilitating condition. If you haven’t seen The King’s Speech, stop reading and put it in your Netflix queue. If you don’t have Netflix, or a DVD player, or are encountering some other road-block in seeing the film, it depicts King George the VI of England and his battle with stammering. It is phenomenal, and that’s not just the overly patriotic ex-pat (mildly oxymoronic?) in me talking, I promise.

Colin Firth as King George VI

Anyway, back to the subject of this piece. I was reading a report on ScienceNOW from the recent AAAS meeting in Washington, D.C. at which researcher Dennis Drayna spoke about the genetic basis of stuttering. Over the last few years, Drayna and his colleagues at the National Institute on Deafness and Other Communication Disorders in Rockville, Maryland, have been investigating a group of genes found to be mutated in a families of stutterers in Pakistan.

Stuttering: history and presentation

Stuttering is characterized by the involuntary repetition or elongation of syllables, sometimes whole words, during speech. In addition, speech is sometimes punctuated by long pauses in which the stammerer is visibly trying to speak but cannot. Normally stuttering first manifests in childhood, and either goes way within a few months or years, or persists into adulthood.

George VI fell into the latter class of people whose stutters followed them out of childhood. In the film we see the effects of stress on his speech. The more pressure he is under to talk, especially in front of an audience, the more difficult it is for him to get his words out. And while we see that speech therapy helped him somewhat, and continues to help sufferers today, it cannot cure the condition.

Historically stuttering has been perceived as a psychological response to emotional trauma. And as with all disorders that have been recognized for centuries, there were some very bizarre treatments, including drinking only from a snail shell and cutting triangular section out of the back of the tongue.

But understanding the underlying cause is often the best way to find a treatment, and that’s where human genetics comes in. Stuttering often runs in families, and children with a stammering parent are three times more likely to develop the same speech impediment. To find the genes responsible Drayna, like other human geneticists, turned to an inbred family of stutterers.

Inbreeding and genetics

Stuttering is a relatively rare disorder, affecting approximately 2.5% of children under the age of five. Since stuttering usually runs in families, chances are there is a recessive mutation in a gene that initiates the disease. So what is a recessive mutation?

In our cells we have two copies of each chromosome, and therefore two copies of every gene. If both copies of that gene are “normal” then the cell is normal. This is referred to as a homozygous situation. If one copy of the gene has a recessive mutation, the cell is heterozygous. In this case, the nature of the mutation comes into play. If the normal gene copy on the other chromosome can compensate for the mutant gene, then the mutation is called recessive and the cell appears normal. If however the normal gene copy cannot compensate, the mutation is considered dominant.

A recessive mutation can lie dormant in a “carrier” individual; that is someone who possesses a normal and a mutant copy of the gene. But if two carriers have children, there is a one in four chance the child will be homozygous for the mutant gene. In this instance the recessive mutation will exert its effect, as there is no normal copy of the gene to take over.

Often recessive mutations are deleterious and ultimately fatal, and therefore offspring with a recessive disease tend not to procreate. This combined with out-breeding (marrying outside of your own family) results in recessive mutations rarely causing disease. In certain cultures however in-breeding is encouraged, and thus rare recessive mutations are retained and propagated.

Interestingly, in-breeding has often been rife amongst royal families in order to maintain power. In ancient Egypt it was the daughter of the Pharoah who retained the throne, and thus she often ended up married to her brother. In more recent times the inter-marrying of European royalty has resulted in a narrowing of the gene pool. Indeed the British royal family has seen couples as close as first cousins marrying.

Needless to say, inbred families have some serious genetic information up for grabs. In the case of stuttering, Drayna’s group went to Pakistan, where marriage between first and second cousins is common (around 70% of all marriages). There they collected data from 46 related families with stutterers and found mutations in three genes, GNPTAG, GNPTG, and NAGPA.

What do these genes do?

Strangely enough these genes all encode proteins critical for the correct function of the lysosome, a kind of cellular garbage disposal system. Lysosomes are organelles (“little organs” within a cell) that break down other worn out organelles as well as invaders such as bacteria and viruses so that they can be recycled and reused by the cell. They contain various enzymes that allow this to occur.

Mutations in GNPTAG, GNPTG, and NAGPA result in the malfunctioning of this waste disposal system, and cause diseases called mucolipidoses. Children with mucolipidosis usually die before the age of ten, and curiously never learn to speak.

However it is important to note that different mutations within the same gene can have differing effects on the function of the encoded protein. For example, imagine building a house. If one of the bricks you use is defective, where you place that brick will affect the integrity of the house in a different way. If the faulty brick is placed in the foundations, the whole house will be affected. However, if it is placed on the top of an internal wall, it is much less likely to have a catastrophic effect on the integrity of the house. The same is true for mutations. They can be massively destructive to the function of the encoded protein, or they can have little to no effect.

It would appear that stutterers have less deleterious mutation in these lysosomal genes than those found in patients with mucolipidoses, though exactly how these mutations exert their effect at the cellular level remains unknown. In order to address these and other questions, Drayna’s group has made mutations in laboratory mice that correspond directly to those found in the Pakistani families he studied. It will be fascinating to see where these studies lead, as part of the experimental design involves analyzing mouse speech patterns.

So could this lead to a cure?

While understanding the root of a condition can often lead to better treatment, there is a key caveat that we must consider; these mutations are not found in all stutterers. When the researchers looked at samples collected from a number of unrelated stutterers they found the mutations only 6% of the time. Clearly there are other causes of this disorder.

However for sufferers with these particular mutations there is hope. Further studies in mouse models will hopefully help us understand the molecular basis of the disease. As stuttering is known to be a neurological disorder, developing small molecules that can cross the blood-brain barrier and interfere with enzyme function will be important. These model mice should also help address the question of cause and effect: Do single mutations in these genes directly cause the mouse to stammer?

But perhaps the most critical question to come from all of this is will Colin Firth finally win his Oscar?

Kang C, Riazuddin S, Mundorff J, Krasnewich D, Friedman P, Mullikin JC, & Drayna D (2010). Mutations in the lysosomal enzyme-targeting pathway and persistent stuttering. The New England journal of medicine, 362 (8), 677-85 PMID: 20147709

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