Genetic Linkage /Positional Cloning In Communication Dis

Deafness &Other Communication Disorders

Investigators

Linked publications & trials

Abstract

In the past year we have discovered the molecular basis of the inability to taste phenylthiocarbamide (PTC) and related substances, which is one of the most intensively studied simple inherited traits in humans. This common sensory deficit has been shown to be correlated with dietary preferences and may be important in food choices and proper nutrition. Despite the discovery of this variation among individuals more than 70 years ago, the genetics of this trait have been controversial, and were ultimately solved by our combined approach of genetic linkage analysis and single nucleotide polymorphism (SNP) association studies. These approaches pinpointed the location of the genetic cause within a member of the TAS2R bitter taster receptor gene family that resides on chromosome 7. This gene encodes a 7 transmembrane G protein coupled receptor expressed on the surface of taste cells, within taste buds on the tongue. Surprisingly, the non-taster form of this gene displays 3 coding sequence differences from the taster form of the gene. We have also discovered three additional forms of this gene. Our studies of the worldwide distribution of these five alleles demonstrate that most of these forms exist primarily in sub-Saharan African populations and only two forms, the major taster and major non-taster forms, emerged from Africa in ancient prehistory and subsequently spread to the remainder of the world. These results were published in a series of papers, first a report by Drayna et al. in Human Genetics and subsequently in our report by Kim et al., published in Science in February of this year. Current studies in our lab are addressing 1) the biochemical function of the different forms of this gene in vitro, 2) the three-dimensional molecular structures of the different forms of the receptor it encodes, and 3) the epidemiology and natural selection factors that have given rise to the current distribution of the various forms of this gene. Additional progress was made this year on the genetics of stuttering. In a study of a large group of North American stuttering families, we identified a location on chromosome 18 that appears to harbor a gene that predisposes individuals to this disorder. While we do not yet have sufficiently precise genetic localization to identify the specific causative gene yet, we have demonstrated that, despite the many difficulties presented by the uncertain genetics of stuttering, we can perform linkage studies and obtain clear evidence for the location of variant genes that contribute to this disorder. These results were published in a report by Shugart et al. in The American Journal of Medical Genetics. We have also identified a remarkable family in Cameroon, in equatorial West Africa, in which stuttering occurs as an apparently simple inherited trait. This family consists of approximately 100 individuals, of whom 45 stutter, approximating a pattern of simple autosomal dominant transmission. We have established a collaborative effort with the Institute of Tropical Medicine in Kumba, Southwest Province and completed review of human subjects protection both in Cameroon and here at the NIH. Diagnosis, sampling, and laboratory studies of this family are now ongoing. Our collaborative studies with investigators at the NINDS also came to fruition this year with the discovery of a gene that was originally identified as the cause of familial vocal fold paralysis, a disorder that can present life-threatening respiratory compromise at birth. Subsequent clinical work up identified other symptoms of distal motor neuronopathy in these patients. Following mapping of the gene to chromosome 2, we discovered mutations in the dynactin gene as the cause of this disorder. This gene encodes a component on the actin-based intracellular transport within neurons. One hypothesis presented by these results is that this defect occurs due to the failure to transport a factor necessary for neuron growth and survival from the peripheral tissue back to the cell nucleus. These results were published in a report by Puls et al. in Nature Genetics in April of this year.