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.”I will write more on this in the next post. Fits well into my picture of stuttering...
But the third mutation causes a larger folding problem and the protein is destroyed just minutes after being made.
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 itCheck 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.
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.
SourceFrom the Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110 and.
AbstractGlcNAc-1-phosphodiester-N-acetylglucosaminidase ("uncovering enzyme" (UCE); EC 18.104.22.168) 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.