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Although the root cause(s) of stuttering remain unknown, evidence has accumulated from twin and adoption studies that genetics plays a role. Dennis Drayna, a geneticist at the National Institute on Deafness and other Communication Disorders (NIDCD), undertook a study to identify the genes involved in the disorder with the ultimate goal to elucidate poorly defined neural structures and functions regulating human speech. Results from the study were reported recently in the New England Journal of Medicine .
The study focused on a Pakistani family in whom previous work had determined that stuttering was linked to the long arm of chromosome 12 (chromosome 12q). In addition to the affected and unaffected members of these families, the study also included 123 Pakistani stutterers who were unrelated and 270 stutterers from the United States and England. Children under the age of eight were excluded, as they often recover from stuttering, as were people with neurologic or psychiatric symptoms. The control group (non-stutterers) consisted of 96 Pakistanis and 276 North American whites.
By sequencing the DNA from chromosome 12q in seven Pakistani stutterers and three Pakistani non-stutterers they homed in on a region of 10 Megabases, containing 87 genes, that was linked to stuttering. The mutations that cosegregated most closely with stuttering — those that were found most often in stutterers — were in a gene called GNPTAB. This gene encodes GlcNAc-phosphotransferase, an enzyme involved in targeting lysosomal enzymes. Like all proteins, lysosomal enzymes are synthesized in the cytoplasm of the cell. GlcNAc-phosphotransferase tags them with mannose-6-phosphate, a sugar molecule that tells the cellular trafficking system to send them to the lysosome. The most common mutation in stutterers from the Asian subcontinent was one that substitutes lysine, an alkaline amino acid, for glutamic acid at position 1,200 in the protein. This amino acid is highly conserved; all vertebrates normally have a glutamic acid at this position, implying that it is important.
Lysosomes are the cellular organelles often likened to a garbage disposal. The enzymes in the lysosome are responsible for degrading extra and expended cellular components, food particles and any viruses and bacteria the cell may have picked up.
After identifying this mutation, the researchers looked at other genes involved in the same pathway — those encoding other proteins responsible for targeting lysosomal enzymes. They found mutations in two other such genes, GlcNAc-1-phosphotransferase subunit gamma (GNPTG) and N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase (NAGPA) in unrelated North American and British stutterers. These mutations were never seen in non-stuttering controls.
Mutations in GNPTAB and GNPTG are known to be associated with the rare inherited lysosomal storage disorders mucolipidosis (ML) types II and III. They are so named because cellular components cannot be degraded properly, and instead end up getting stored in the lysosome. These disorders are characterized by developmental delay; joint, heart, liver, and skeletal system problems; and often, speech deficits. Interestingly, GNPTG is highly expressed in areas of the mouse brain known to be associated with emotion: the hippocampus and cerebellum. Emotional state can definitely impact stuttering. Mutations in NAGPA have never been associated with any human malady.
How, then, did the stutterers get off relatively easy — if they have mutations in the same genes, why don’t they have the same problems? ML disorders are inherited in a recessive manner, so are caused by having two copies of the mutated gene. These stutterers have one mutated copy and one normal copy. Moreover, the mutations they found — which are not present in people with ML II or III — result in an altered protein, whereas those that cause ML II and III yield a truncated protein. In addition, they found mutant GNPTAB in members of the Pakistani family who did not stutter. This indicates that the mutation has incomplete penetrance, meaning that it is possible to have the mutated gene, but not necessarily stutter. The mutation increases the risk of stuttering rather than causing it directly in every case.
Approximately 1% of Americans — roughly 3 million people — stutter. In their future work, Dr. Drayna and colleagues intend to find the percentage of the general population with one of these mutations, and to figure out exactly how mutations in these enzymes impact the enzyme’s activity.
For more information on theNational Institute on Deafness and other Communication Disorders, please visit www.nidcd.nih.gov.
- Kang et al. Mutations in the lysosomal enzyme-targeting pathway and persistent stuttering. N Engl J Med. 2010 Feb 25;362(8):677-85. Epub 2010 Feb 10.