GNPTAB と GNPTG は重症の代謝性疾患と関連している。ライソソーム病と呼ばれ、脳を含めた全身で問題が生じる。代謝疾患として発病するには2つのコピーが必要だが、1つのコピーと吃音が関連している。3つ目の遺伝子異常はこの2つに密接に関連している。
Page last updated at 00:01 GMT, Thursday, 11 February 2010
Genes behind stammering uncovered
Early intervention can help children overcome stammering
Stammering has long been recognised to run in families, but scientists now say they have identified three genes which may cause the problem in some people.
They believe that mutations which have already been tied to metabolic disorders may also affect the way in which parts of the brain function.
The study involving cases in Pakistan, the US and England appears in the New England Journal of Medicine.
Stammering affects about 1% of all adults worldwide.
Those affected repeat or prolong sounds, syllables or words, disrupting the normal flow of speech.
With early intervention children who stammer can overcome the problem, while for adults therapies are based on reducing anxiety and regulating breathing to improve speech.
But the team from the National Institute on Deafness and Other Communication Disorders (NIDCD) hopes its discovery may pave the way for new treatments.
Nearly one in ten of the sufferers examined were found to have a mutation in one of three genes.
Two of these, GNPTAB and GNPTG, have already been linked to two serious metabolic diseases in which components of cells are not effectively recycled.
In addition to finding new forms of treatment, we hope this may help us identifying those children at risk of persistent stammering as it is only through early intervention that they have a chance of recovering fluent speech
British Stammering Association
These disorders, known as lyposomal storage disorders, lead to a build-up of a potentially dangerous substance which can cause problems in almost every area of the body, including the brain.
People with this defective gene need two copies to develop the metabolic disorder, but one copy appears to be associated with stammering.
A third defective gene, which is closely related to the other two, was also found among stammerers but not among the controls.
"For hundreds of years, the cause of stuttering has remained a mystery for researchers and health care professionals alike, not to mention people who stutter and their families," said James Battey, head of the NIDCD.
"This is the first study to pinpoint specific gene mutations as the potential cause of stuttering, and by doing so, might lead to a dramatic expansion in our options for treatment."
The metabolic disorders pinpointed can be treated by injecting a manufactured enzyme into a person's bloodstream to take the place of the enzyme the body fails to produce. It is possible stammering, if confirmed to be caused by the same defect, would respond to the same treatment.
The British Stammering Association welcomed the findings.
"It is just the latest in a string of recent discoveries highlighting the fact that the cause of stammering is physiological - a symptom that, for whatever reason, the brain's neural circuits for speech are not being wired normally," said its director Norbert Lieckfeldt.
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"This puts into sharp relief the bullying and ridicule people who stammer often experience, as opposed to people experiencing for instance mobility disabilities.
"In addition to finding new forms of treatment, we hope this may help us identifying those children at risk of persistent stammering as it is only through early intervention that they have a chance of recovering fluent speech."
Published at www.nejm.org February 10, 2010 (10.1056/NEJMoa0902630)
Mutations in the Lysosomal Enzyme–Targeting Pathway and Persistent Stuttering
Changsoo Kang, Ph.D., Sheikh Riazuddin, Ph.D., Jennifer Mundorff, M.A., Donna Krasnewich, M.D., Ph.D., Penelope Friedman, M.D., James C. Mullikin, Ph.D., and Dennis Drayna, Ph.D.
Background Stuttering is a disorder of unknown cause characterized by repetitions, prolongations, and interruptions in the flow of speech. Genetic factors have been implicated in this disorder, and previous studies of stuttering have identified linkage to markers on chromosome 12.
Methods We analyzed the chromosome 12q23.3 genomic region in consanguineous Pakistani families, some members of which had nonsyndromic stuttering and in unrelated case and control subjects from Pakistan and North America.
Results We identified a missense mutation in the N-acetylglucosamine-1-phosphate transferase gene (GNPTAB), which encodes the alpha and beta catalytic subunits of GlcNAc-phosphotransferase (GNPT [EC 188.8.131.52 [EC] ]), that was associated with stuttering in a large, consanguineous Pakistani family. This mutation occurred in the affected members of approximately 10% of Pakistani families studied, but it occurred only once in 192 chromosomes from unaffected, unrelated Pakistani control subjects and was not observed in 552 chromosomes from unaffected, unrelated North American control subjects. This and three other mutations in GNPTAB occurred in unrelated subjects with stuttering but not in control subjects. We also identified three mutations in the GNPTG gene, which encodes the gamma subunit of GNPT, in affected subjects of Asian and European descent but not in control subjects. Furthermore, we identified three mutations in the NAGPA gene, which encodes the so-called uncovering enzyme, in other affected subjects but not in control subjects. These genes encode enzymes that generate the mannose-6-phosphate signal, which directs a diverse group of hydrolases to the lysosome. Deficits in this system are associated with the mucolipidoses, rare lysosomal storage disorders that are most commonly associated with bone, connective tissue, and neurologic symptoms.
Conclusions Susceptibility to nonsyndromic stuttering is associated with variations in genes governing lysosomal metabolism.
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