Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS025631-02
Application #
3410939
Study Section
Neurology C Study Section (NEUC)
Project Start
1988-02-01
Project End
1991-01-31
Budget Start
1989-02-01
Budget End
1990-01-31
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost

  Institution

Name
University of California Irvine
Department
Type
Schools of Medicine
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697

  Publications

Marsh, J L; Walker, H; Theisen, H et al. (2000) Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila. Hum Mol Genet 9:13-25
Raffioni, S; Zhu, Y Z; Bradshaw, R A et al. (1998) Effect of transmembrane and kinase domain mutations on fibroblast growth factor receptor 3 chimera signaling in PC12 cells. A model for the control of receptor tyrosine kinase activation. J Biol Chem 273:35250-9
Thompson, L M; Raffioni, S; Wasmuth, J J et al. (1997) Chimeras of the native form or achondroplasia mutant (G375C) of human fibroblast growth factor receptor 3 induce ligand-dependent differentiation of PC12 cells. Mol Cell Biol 17:4169-77
Tavormina, P L; Shiang, R; Thompson, L M et al. (1995) Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet 9:321-8
Tavormina, P L; Rimoin, D L; Cohn, D H et al. (1995) Another mutation that results in the substitution of an unpaired cysteine residue in the extracellular domain of FGFR3 in thanatophoric dysplasia type I. Hum Mol Genet 4:2175-7
Shiang, R; Thompson, L M; Zhu, Y Z et al. (1994) Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78:335-42
(1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell 72:971-83
Altherr, M R; Wasmuth, J J; Seldin, M F et al. (1992) Chromosome mapping of the rod photoreceptor cGMP phosphodiesterase beta-subunit gene in mouse and human: tight linkage to the Huntington disease region (4p16.3). Genomics 12:750-4
Liptay, S; Schmid, R M; Perkins, N D et al. (1992) Related subunits of NF-kappa B map to two distinct loci associated with translocations in leukemia, NFKB1 and NFKB2. Genomics 13:287-92
Wilcox, A S; Warrington, J A; Gardiner, K et al. (1992) Human chromosomal localization of genes encoding the gamma 1 and gamma 2 subunits of the gamma-aminobutyric acid receptor indicates that members of this gene family are often clustered in the genome. Proc Natl Acad Sci U S A 89:5857-61

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