Genetic linkage analysis has been an extraordinary tool for identifying disease genes. Over the past ten years, linkage analysis has played a key role in the cloning of several disease. Shortly through the efforts of the Human Genome Initiative, maps of highly polymorphic markers with spacing of 5-10 cM will be available for all chromosomes. These accurate and well defined maps will allow for the efficient screening of linkage of most single gene disorders. In addition, they will provide the foundation for the genetic dissection of diseases with complex patterns of inheritance. The ability to tease out both major gene and moderate effects and their contributions to the etiology of the disorder in question could serve as the first step in combatting the more common human afflictions. The goal of the present proposal is to continue our genetic mapping studies of neurogenetic disorders. Using our past experiences, resources and successes as a guideline we will localize and identify major gene affects in a number of diseases. We will employ a systematic screening approach that combines the use of well-mapped highly polymorphic marker systems with expert clinical and state-of-the art genetic epidemiological tools. We will begin out studies by searching for the chromosomal localization in a number of disorders such as nonchromosome 1 linked CMT2, oculopharangeal muscular dystrophy, and non- chromosome 4 linked facio-scapular humeral muscular dystrophy (FSHD) and unlinked autosomal dominant limb girdle muscular dystrophy (LGM1). We will examine and characterize the extent of heterogeneity in LGM1 and FSHD. Concurrent with the screening of above disorders, we will continue to evaluate and collect DNA on new disorders such as Native American Myopathy and Haw River Syndrome. We will also develop during the course of the grant several complex disease data sets (i.e. neural tube defects and familial narcolepsy). These diseases will be then be incorporated into the genomic screen in subsequent years. Once linkage is established for a particular disorder, we will proceed with our fine mapping objectives in preparation for the application of molecular biological tools to identify the basic defect. Finally, we will investigate both theoretical and applied statistical approaches to the use of linage disequilibrium in mapping diseases. A successful linkage in any of these disorder will represent the first step towards the long range goal of treatment of these affections.

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Duke University
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