The long term objective of this proposal is to understand the molecular and biochemical basis for the inherited neurological disorder, Huntingtons Disease (HD). As in the case with most inherited neurologic disorders, nothing is known about the biochemical basis of HD or the nature of the affected gene. The only real hope of understanding the disease and developing effective therapies, is to isolate and characterize the normal and defective alleles. The major aim of this project is to isolate the HD gene, using the strategy of reverse genetics. A large number of single copy DNA fragments from the distal portion of the short arm of chromosome 4, the region where the HD gene is located, have been isolated, will be regionally mapped using somatic cell hybrids, and used to compile a long range restriction map of several million base pairs of DNA around the HD gene. DNA fragments that are close to, and on opposite sides of the HD gene will be identified using several approaches. Single copy DNA fragments spanning the region containing the HD gene will be analyzed to determine which represent portions of expressed genes and whether any detect DNA sequence rearrangements in patients with HD. Genomic and cDNA clones representing expressed genes in the vicinity of the HD gene will be examined to determine if their expression and/or structure is altered in patients with the disease. If such alterations are found, the candidate gene will be isolated from genomic DNA libraries from and HD patient and the structure and sequence compared to the corresponding gene from unaffected individuals. The isolation of the HD gene and an understanding of its function will provide the capability for 100% accurate preclinical diagnosis of this late age of onset disorder and may well lead to the development of effective therapies to prevent or delay onset of symptoms.