Through the study of a unique Venezuelan Huntington's disease kindred the gene for HD was localized to chromosome 4p using new molecular genetic techniques; homozygotes for the disease were identified """"""""and the phenomenon of complete dominance"""""""" genetically documented for the first time in human medical genetics; key genetic recombinants were found, permitting more precise chromosomal localization of the HD gene and high resolution geneiic and physical mapping of the candidate region; and the HD gene itself was discovered to be an unstable trinucleotide CAG repeat in a novel protein called """"""""huntington."""""""" The Venezuelan kindred now has an unparalleled role to play in this next phase of understanding the disorder, from the molecular behavior of the repeat to its clinical manifestations. It is the only existing kindred in which the HD allele has been inherited from a progenitor and passed through ten generations and hundreds of meioses, eliminating allelic heterogeneity and ensuring that all those in the kindred who have inherited the HD gene have the identical allele and terrain surrounding it. The enormity of the kindred, over 14,000 people, the huge sibship size, the shared background genes and environment, and the cooperativity of family members provide an unmatched research resource.
The aims of the project are: 1 ) To understand the relationship between genotype and phenotype in their natural habitat, unbiased by ascertainment. To study the behavior of the CAG repeat segregating on a single haplotype as it has already afflicted over 400 people and as it now threatens 4,697 at risk children, 1,653 of whom will die of the disease in the ensuing years. To learn how genetic characteristics contribute to clinical consequences and seek to explain why people with the same number repeat units have widely varying clinical manifestations. 2) To discover modifiers, either genetic or environmental, that may regulate the frequency or magnitude of CAG expansion or influence phenotypic expression. 3) To analyze juvenile cases in more detail and the fathers who produce them; to understand what governs the plasticity of the repeat and why huge expansion produce juvenile onset. 4) To characterize genetically and phenotypically the growing population of homozygotes and learn how they cope with two doses of expanded alleles. The Venezuelan HD kindred is the largest single source of these rare homozygous individuals in the world; 8 have been identified already and 28 should be in the kindred. 5) To collect tissue samples that can provide insight on the expansion process, including lymphoblast lines and sperm samples. As a prospective, longitudinal study, to examine the effect of age, disease duration, birth order or environmental factors on sperm, in which mosaicism has been identified. 6) To collect brain and other post-mortem tissues from genetically and clinically well characterized members of the kindred to understand how the huntington protein specifically devastates striatal neurons. These tissues will enable us to tie together the behavior of the gene, its target in the brain and the clinical repercussions these two produce. 7) To develop a molecular cognitive neuroscience approach to understanding how the expansion produces profound cognitive and behavioral disturbances. To develop a more precise neuropsychological battery to ascertain capacities and limitations that are germane to the underlying neuropathology. 8) To explore how psychiatric and cognitive symptomatology can also be regulated by the expanded repeat or some other genetic modifiers. 9) To characterize the kind-red for common disorders and genetic traits or markers.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Study Section
Neurology A Study Section (NEUA)
Program Officer
Oliver, Eugene J
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Hereditary Disease Foundation
Santa Monica
United States
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Brocklebank, D; Gayán, J; Andresen, J M et al. (2009) Repeat instability in the 27-39 CAG range of the HD gene in the Venezuelan kindreds: Counseling implications. Am J Med Genet B Neuropsychiatr Genet 150B:425-9
Leeflang, E P; Tavare, S; Marjoram, P et al. (1999) Analysis of germline mutation spectra at the Huntington's disease locus supports a mitotic mutation mechanism. Hum Mol Genet 8:173-83
Leeflang, E P; Zhang, L; Tavare, S et al. (1995) Single sperm analysis of the trinucleotide repeats in the Huntington's disease gene: quantification of the mutation frequency spectrum. Hum Mol Genet 4:1519-26
Persichetti, F; Ambrose, C M; Ge, P et al. (1995) Normal and expanded Huntington's disease gene alleles produce distinguishable proteins due to translation across the CAG repeat. Mol Med 1:374-83
(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
Locke, P A; MacDonald, M E; Srinidhi, J et al. (1993) A genetic linkage map of the chromosome 4 short arm. Somat Cell Mol Genet 19:95-101
Haines, J L; Guillemette, W; Rosen, D et al. (1993) A genetic linkage map of chromosome 21: a look at meiotic phenomena. Prog Clin Biol Res 384:51-61
Gusella, J F; MacDonald, M E; Ambrose, C M et al. (1993) Molecular genetics of Huntington's disease. Arch Neurol 50:1157-63
Kwiatkowski, D J; Henske, E P; Weimer, K et al. (1992) Construction of a GT polymorphism map of human 9q. Genomics 12:229-40
Scott, H S; Nelson, P V; MacDonald, M E et al. (1992) An 86-bp VNTR within IDUA is the basis of the D4S111 polymorphic locus. Genomics 14:1118-20

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