Abstract

The long term goals of this project are to isolate the Huntington's disease (HD) gene, identify the most common mutation in the gene which causes the disease and, ultimately, understand at the molecular level how a mutant allele at this locus produces the neuropathology of the disease in heterozygotes. A combination of physical mapping strategies will be employed to compile a very high resolution physical map of a region of about 2.5 Mb of DNA which now appears to be the most narrowly defined location of the disease gene. This will include several approaches to rapidly isolate and map many new DNA probes throughout this segment of chromosomal band 4p16.3. Somatic cell hybrids which retain chromosomes 4 from several important recombinants with HD will be isolated and extensively characterized. This provides a means for unequivocal haplotyping of a large number of polymorphic loci which will allow a more precise locilization for the disease gene to be made. All of the DNA from the minimal physical region shown to contain the HD gene will be isolated in overlapping cosmid and YAC clones. The cloned DNA will be thoroughly examined to identify genomic sequences likely to represent transcribed regions. Full lengih cDNA clones and genomic clones representing candidates for the HD gene will be isolated and used to compare the structure, sequence and expression of these genes in normal individuals, HD heterozygotes and HD homozygotes in order to identify a specific alteration which represents the most common HD mutation. The achievement of this goal will eventually lead to an understanding of the function of the normal HD gene produce and provide insight into how the presence of a mutant gene product disorder. This information will hopefully point to possible completely prevent the 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 #
2R01NS025631-04
Application #
3410938
Study Section
Neurology C Study Section (NEUC)
Project Start
1991-02-01
Project End
1998-01-31
Budget Start
1991-02-01
Budget End
1992-01-31
Support Year
4
Fiscal Year
1991
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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