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From: Dennis Drayna
Date: 21 Oct 2011
Time: 13:58:27 -0500
Remote Name: 165.112.47.66
Dear Ryan - These issues comprise the fundamental basis of our initial discovery of a mutation in the GNPTAB gene as the cause of stuttering. In a group of 44 Pakistani families, all of whom contained multiple individuals with persistent stuttering, we demonstrated co-inheritance of genetic markers in one specific place on chromosome 12 with stuttering. This is called genetic linkage. Linkage occurs because the markers reside very close to the gene that causes stuttering in these families. Since all of the markers showing linkage are on chromosome 12, we knew such a gene resided in this region. The fact that we achieved so-called genome-wide statistical significance for linkage indicated that our evidence for this linkage was overwhelming. The region showing linkage to stuttering in this group of families spanned about 10 million base pairs (letters in the DNA code), containing some 87 identifiable genes. We undertook a very laborious evaluation of all of these genes in one very large Pakistani family with many cases of stuttering. We found many variants in these genes in different members of this large family. However a single variant went along best (i.e. was most tightly co-inherited) with stuttering in this family. This variant was a mutation in a gene called GNPTAB. When we looked at this position in the GNPTAB gene in all 44 Pakistani stuttering families that were used in the original linkage study, we found the same mutation in this same gene in the stuttering individuals (but not in the normal members) in 4 of these families. This mutation was not found in 500 well characterized neurologically normal control individuals. Examination of the GNPTAB gene in individuals with persistent stuttering from populations worldwide revealed another 6 different mutations in this gene, none of which ever occurred in our 500 normal control subjects.