Wednesday, November 23, 2011

Stuttering research goes biochemical

Stuttering research is entering a new phase, the biochemical phase. As far as I know, it's the first research that deals with fundamental biochemical aspects of our brain that are linked to stuttering via genetics research.

Kornfeld on what the three mutations found by Dryana's group do to possibly 10% of us:
...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.
I will write more on this in the next post. Fits well into my picture of stuttering...

Kornfeld on therapy: (so you can keep your dream of a cure alive! ,-)
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.
Check out this article describing work in Kornfeld's lab, and the corresponding article by Lee et al. on Analysis of mannose 6-phosphate uncovering enzyme mutations associated with persistent stuttering.


From the Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110 and.


GlcNAc-1-phosphodiester-N-acetylglucosaminidase ("uncovering enzyme" (UCE); EC is a Golgi enzyme that mediates the second step in the synthesis of the mannose 6-phosphate lysosomal targeting signal on acid hydrolases. Recently, three mutations (two missense and one deletion/frameshift) in the NAGPA gene that encodes UCE have been identified in individuals with persistent stuttering. We now demonstrate that each mutation leads to lower cellular UCE activity. The p.R328C mutation impairs folding in the endoplasmic reticulum, resulting in degradation of a significant portion by the proteasomal system. The p.H84Q mutation also impairs folding and, in addition, decreases the specific activity of the enzyme that folds sufficiently to traffic to the Golgi. The p.F513SfsX113 frameshift mutation adds 113 amino acids to the C terminus of the cytoplasmic tail of the protein, including a VWLL sequence that causes rapid degradation via the proteasomal system. These biochemical findings extend the genetic data implicating mutations in the NAGPA gene in the persistent stuttering phenotype.


Gerald Maguire, MD said...

Hi, Tom. This study provides tremendous guidance on developing a specifically targeted pharmacologic approach to stuttering. Our neurotransmitter treatments are likely working much downstream in the process. I'm assembling a team here at my university ( pediatric-geneticist, basic science pharmacologist and psychiatrist) to review these underlying abnormalities and hopefully develop targeted therapies. Much work needs to be done but we may now have a strong foundation from where to begin.

Satyendra said...

Congrats Gerald! At last some logical approach is being made in this field full of subjective claims...

Anonymous said...

Another thing about this gene is that it is not consistent with the male to female ratio. There were only 2 people with one of the mutations that did not stutter and both were women, but the sex ratio is still approximately 1:1. Could this indicate that these mutations are responsible for a much larger percentage of female stuttering than male stuttering? Another thing mentioned frequently without reference to gender is the recovery rate. It seems like the sex ratio is more like 1:1 for incidence, but 4:1 for prevalence. The recovery rate for each gender is different yet the standard 80% figure is mentioned constantly. For stuttering overall, this is a 100% correct figure but when assessing the chances a given child will recover it is 100% wrong. Or maybe I have a misunderstanding somewhere.

Tom Weidig said...

@Anonym: Interesting point

I only guessing here. But the mutation is probably equally present across the sexes. And they start stuttering in equal numbers, but the recovery is higher in girls because they have more brain resources to cope.

I also think that due to the extra half chromosome woman have, it is more likely that some of these genes are counteracting a mutation.

But I didn't understand your last point.

Anonymous said...

See this post on the ISAD conference by Drayna He says the gender ratio is about 1:1, but there is still some tendency for females to recover. So the mutation has to be responsible for a larger percentage of female stuttering and a smaller percentage of male stuttering than reported.

The figure that 80% recover is also wrong for an individual child because recovery depends on their gender. The prevalence for each gender seems to be about 5%. But the sex ratio becomes 4:1 into adulthood. So using the 1% figure .8 percent of the population are male stutterers and .2 are female. Say the population is equally male and female. So the male recovery rate is 1-.8*2/2.5 and for females it is 1-.2*2/2.5. For males it's about 64% and females it's 84%. The real way to determine this is to go measure it, but the point is male and female stuttering must be considered separately.

The normal control group in genetic studies may have neurologically normal females with the genes that cause
male stuttering. The stuttering females are only going to have a fraction of the mutations, the ones their additional brain resources can't overcome. Really male and female stuttering should be compared separately against male and female control groups.

Anonymous said...

Correction approximate recovery is about 36% for males if the incidence is equal among genders.

Anonymous said...

For the second sentence in the second paragraph prevalence should be incidence.

Anonymous said...

I apologize for there being so many errors in my comment. The approximate recovery rates for males and females are actually 1.7/2.5 (68%) and 2.3/2.5 (92%) respectively.