In our studies of stuttering, we have been working with a group of Pakistani stuttering families in which we have previously shown that a gene located on chromosome 12 is implicated in the cause of this disorder. We have enrolled several cohorts of subjects for case-control studies designed to identify the specific causative gene within this region on chromosome 12. These cohorts consist of 100 unrelated Pakistani stutterers and 100 population-matched controls, and 300 European unrelated cases and 300 documented neurologically normal controls. We performed an association study in these subject populations using 500 single nucleotide polymorphisms (SNPs) and identified several sub-regions of the interval on chromosome 12 that show evidence of being at higher frequency in the stuttering cases. We are currently evaluating several genes in this region in greater detail. We have also continued our studies in a group of families in Cameroon, West Africa, in which stuttering occurs consistent with a simple inherited trait. We have previously obtained evidence that a gene on chromosome 1 is responsible in the largest of these families, but follow-up genotyping in this region, plus a subsequent new genome-wide linkage analysis, performed with the next generation of single nucleotide polymorphism (SNP) markers, failed to confirm this linkage. We have now identified significant linkage on chromosome 15, and we are working to refine this linkage location and identify candidate genes in this region.? Our studies of deficits in the sense of taste currently focus on sweet taste. During the past year, we have derived clones of all 18 different forms of the human T1R2 sweet taste receptor protein that exist in populations world wide, and cloned these into mammalian cell expression vectors for cell-based studies of sweet taste receptor function. While all receptors appear to be functional in ex vivo calcium release assays in transfected cells, some forms clearly posess different sensitivity to sweet agonists. In the past year, we have identified one naturally occurring African-specific haplotype that clearly conveys a reduced sensitivity to sucrose and other carbohydrate sweeteners. This haplotype differs from the most common haplotype at three amino acid positions. We have performed a study to dissect this in detail, and have found that just one of these three amino acid differences, substituting a glutamine for the typical lysine at amino acid position 689, is responsible for this reduced sensitivity. ? We are also testing human subjects for their sensitivity to a variety of sugars and artificial sweeteners, and obtaining DNA from these subjects to identify the forms of the sweet taste receptor gene they carry. The goal of these studies is to identify the genetic basis of differences in sweet taste perception between different individuals. We have made psychophysical measurements of sucrose sensitivity of 165 unrelated normal subjects, and shown that individuals are stable in the ability to detect this sugar, and that there is wide variation among individuals in their sweet perception worldwide. We have obtained DNA sequence information from the T1R2 and T1R3 genes (which together encode the major sweet receptor) in these subjects, and have discovered that two SNPs upstream of the T1R3 coding sequence exert a significant effect on sucrose sensitivity in these subjects. These SNPs reside within the core consensus sequences for transcription factor binding sites, and together they account for approximately 8% of the variation in sucrose perception in the population. We hypothesize that these variants act by altering the transcription level of the T1R3 gene, and we are working to demonstrate this in an ex-vivo transcription reporter assay. ? Our studies on deficits in auditory pitch perception (tune deafness) are continuing. In the past year, we have collaborated with Dr. Allen Braun of the NIDCD to show that our group of tune deaf subjects display electroencephalographic (EEG) event-related potentials indicating they perceive wrong notes in a musical melody, despite the fact that they are not consciously aware of such wrong notes. This phenomenon may be analogous to blind sight in the visual system, but it occurs in a much larger group of individuals (tune deafness affects over 1% of the population), who have not sustained frank injury to the brain.
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