Dr Dennis Drayna is the leader of a project that has identified three related genes that may trigger stammering.
Our research paper was published in February in the New England Journal of Medicine, and is the first to pinpoint specific gene mutations as the potential cause of stammering. We found mutations in three related genes in a proportion of people who stammer but not in our fluent 'controls'. We estimate that around 9% of stammering that occurs with a family history has a mutation in one of these genes. In the United States, the proportion of stammering with a family history appears to be something like 50-70%.
Stammering tends to run in families, and researchers have long suspected a genetic component in this disorder. Previous studies we did in a group of families from Pakistan indicated a place on chromosome 12 that was likely to harbor a gene variant associated with stammering.
In our latest research, we refined the location of this place on chromosome 12 and focused our efforts on this more precisely localized site. This led us to identify mutations in a gene known as GNPTAB in the members of a large Pakistani family who stammer. Analyzing genes of further individuals from Pakistan, the United States and England, we found that some of those who stammered possess the same mutation as the large Pakistani family. We also found three other mutations in the same gene which showed up in several unrelated individuals who stammer but not in the controls.
We also identified mutations in two additional related genes that did not occur in normal control individuals. One of these genes is called GNPTG. The product of this gene combines with the product of the GNPTAB gene to form an enzyme that is present in all cells of the body. In addition, all cells contain a second enzyme called NAGPA, which acts at the next step in their metabolic process, and thus these enzymes work hand-in-hand. The link between the genes meant that, once we found mutations in the GNPTAB gene, the GNPTG and NAGPA genes were the next logical place for us to look. Indeed, when we examined these two genes, we found mutations in individuals who stammer, but we never found mutations in control groups.
So what do these enzymes do? They are responsible for putting a signal on a large group of different enzymes (about 60 in all) that help to break down and recycle cellular components. This break-down happens inside a special compartment in the cell called the lysosome, which digests materials that the cell wishes to recycle as part of its normal metabolism. The GNPTAB/G enzyme and the NAGPA enzyme work to put a 'targeting signal' on all these 60 enzymes. This signal tells the cell to transport these enzymes and put them into the lysosome where they belong.
Mutations in the GNPTAB and GNPTG genes have already been tied to two serious diseases called ML disorders. They are 'lysosomal storage disorders', where improperly recycled cell components accumulate in the lysosome. Large deposits of these substances ultimately cause joint, skeletal system, heart, liver, and other health problems as well as developmental problems in the brain. They are also known to cause problems with speech. Why don't people with the stammering mutations have more serious complications? We think one reason is because ML disorders are so-called recessive genetic disorders; you need to have two copies of a defective gene in order to get the disease. Most of the individuals in our study who stammered had only one copy of the mutation. Also, with stammering, the protein is still made, but it's not made exactly right. With ML diseases, the proteins typically aren't made at all.
Crucial future research
One of our goals is now to conduct a worldwide larger-scale study to better determine the percentage of people who carry one or more of these mutations. We are also aiming to determine specifically how the mutations affect the function of the enzymes, and just which cells in the brain are affected by the mutations in such a way as to produce stammering. Regarding this last point, we have some hints suggesting they may be cells which are involved in emotion - many people feel that anxiety for example has a strong effect on stammering.
In addition, it's clear that these mutations occur in only a fraction of people who stammer, and obviously much stammering is not accounted for by our findings. However, we've continued our genetic studies and have now found the location of additional genes which are not yet published. We're hoping these additional genes will account for a larger fraction of stammering, and give us additional insights into the causes of the disorder. Overall, we have much to learn before we fully understand how this inherited disorder of metabolism can lead to stammering.
New avenues for treatment?
Our findings open new research avenues into possible treatments for stammering. For example, current treatment for some lysosomal storage disorders involves injecting manufactured enzyme into a person's bloodstream to replace the missing enzyme. So enzyme replacement therapy is a distant but exciting future possibility for treating this group of people who stammer.
enzyme replacement therapy is a distant but exciting future possibility for treating this group of people who stammer
All of the research subjects in our study were people with a persistent, often life-long stammer. This is consistent with an inherited disorder in these individuals. Our findings probably do not apply to the majority of stammering that only occurs for a short period of time in young children.
We've also addressed the question of whether stammering is simply one visible manifestation of ML disorders. We've been able to perform a detailed medical examination of a few of the individuals with mutations in these genes and so far, none of them display any signs or symptoms of ML disorders. So, while the ML disorders are often very severe medical conditions, those who stammer do not appear to be at risk for these diseases.
Dr Dennis Drayna is a geneticist and Senior Investigator at the National Institute on Deafness and Other Communication Disorders in Maryland, USA.
Kang C et al (2010). Mutations in the lysosomal enzyme-targeting pathway and persistent stuttering. NEJM 362:677-85. doi:10.1056/NEJMoa0902630
From the Summer 2010 issue of Speaking Out, pages 14-15.