Essential tremor (ET), the most common movement disorder in humans, significantly compromises the livelihood or social function of at least 85 percent of the 4 million individuals affected with the disease in the United States. Aggravated by emotions, hunger, fatigue and temperature extremes, the condition may cause a functional disability or even incapacitation. The main clinical feature of ET is postural tremor of the arms, but the head, legs, trunk, voice, jaw, and facial muscles also may be involved. The majority of cases are familial and the disease is usually an autosomal dominant trait with incomplete penetrance. The identification of two susceptibility loci on chromosomes (chr) 2p22-p25 (ETM) and chr 3q13.1 (FET1) implies that ET is genetically heterogeneous. We originally identified the ETM locus in a single American family of Czech descent with pure ET, and later refined the location of the ETM gene to 9.1 centiMorgan region by genotyping three additional families with a similar phenotype. The long-term objectives of the proposal are to identify the other ET susceptibility loci by linkage analysis and to characterize these genes by positional cloning techniques.
The specific aims are the following: 1). Collect additional individuals and families with ET. 2). Define the minimal critical region (MCR) that contains ET genes by identifying key recombinants. 3). Construct a high-resolution physical map (contig) of the MCR. 4). Isolate the genes within the contig and evaluate these candidates for disease-causing mutations. The results of this research will enhance our understanding of the human motor system in general and the pathogenesis of tremor in particular. Because current pharmacological treatments for ET have limited efficacy and often become ineffective with advancing disease, identifying the genes that cause ET will facilitate the development of more effective therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS039353-02
Application #
6343910
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Heemskerk, Jill E
Project Start
2000-01-01
Project End
2004-12-31
Budget Start
2001-01-29
Budget End
2001-12-31
Support Year
2
Fiscal Year
2001
Total Cost
$167,979
Indirect Cost
Name
Mid-Hudson Family Health Institute
Department
Type
DUNS #
City
New Paltz
State
NY
Country
United States
Zip Code
12561
Higgins, Joseph J; Lombardi, Roni Q; Pucilowska, Joanna et al. (2006) HS1-BP3 gene variant is common in familial essential tremor. Mov Disord 21:306-9
Higgins, J J; Lombardi, R Q; Pucilowska, J et al. (2005) A variant in the HS1-BP3 gene is associated with familial essential tremor. Neurology 64:417-21
Higgins, J J; Lombardi, R Q; Tan, E K et al. (2004) Haplotype analysis at the ETM2 locus in a Singaporean sample with familial essential tremor. Clin Genet 66:353-7
Higgins, Joseph J; Lombardi, Roni Q; Pucilowska, Joanna et al. (2004) Integrated physical map of the human essential tremor gene region (ETM2) on chromosome 2p24.3-p24.2. Am J Med Genet B Neuropsychiatr Genet 127B:128-30
Higgins, Joseph J; Jankovic, Joseph; Lombardi, Roni Q et al. (2003) Haplotype analysis of the ETM2 locus in familial essential tremor. Neurogenetics 4:185-9
Higgins, J J; Loveless, J M; Goswami, S et al. (2001) An atypical intronic deletion widens the spectrum of mutations in hereditary spastic paraplegia. Neurology 56:1482-5