Abstract
Kennedy disease is a disorder with progressive motor neuron degeneration that is caused by trinucleotide repeat expansion in the androgen receptor gene. The disease mechanism likely involves toxicity of an expanded polyglutamine tract in the androgen receptor protein. This mechanism is probably shared by other neurodegenerative disorders with polyglutamine expansion, including Huntington disease. Attempts at reproducing the Kennedy disease phenotype by introducing the expanded androgen receptor into cultured neuronal cells and transgenic animals have thus far been unsuccessful, but recently developed model systems with other expanded polyglutamine constructs should allow the pathogenesis of these diseases to be elucidated.
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REFERENCES
Bingham PM, Scott MO, Wang S, et al (1995) Stability of an expanded trinucleotide repeat in the androgen receptor gene in transgenic mice. Nature Genet 9: 191–196.
Brooks BP, Paulson HL, Merry DE, et al (1997) Characterization of an expanded glutamine repeat androgen receptor in a neuronal cell culture system. Neurobiol Disease, in press.
Burright EN, Clark HB, Servadio A, et al (1995) SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell 82: 937–948.
Choong CS, Kemppainen JA, Zhou Z, Wilson EM (1996) Reduced androgen receptor gene expression with first exon CAG repeat expansion. Mol Endocrinol 10: 1527–1535.
Edwards A, Hammond HA, Jin L, et al (1992) Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups. Genomics 12: 241–253.
Fischbeck KH, Ionasescu V, Ritter AW, et al (1986) Localization of the gene for X-linked spinal muscular atrophy. Neurology 36: 1595–1598.
Fischbeck KH, Souders D, La Spada A (1991) A candidate gene for X-linked spinal muscular atrophy. Adv Neurol 56: 209–213.
Harding AE, Thomas PK, Baraitser M, et al (1982) X-linked recessive bulbospinal neuronopathy: a report of ten cases. J Neurol Neurosurg Psychiatry 45: 1012–1019.
Huntington Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington disease chromosomes. Cell 72: 971–983.
Ikeda H, Yamaguchi M, Sugai S, et al (1996) Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo. Nature Genet 13: 196–202.
Kawaguchi Y, Okamoto T, Taniwaki M, et al (1994) CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nature Genet 8: 221–228.
Kennedy WR, Alter M, Sung JH (1968) Progressive proximal spinal and bulbar muscular atrophy of late onset: a sex-linked recessive trait. Neurology 18: 671–680.
Koide R, Ikeuchi O, Onodera O, et al (1994) Unstable expansion of CAG repeats in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nature Genet 6: 9–13.
La Spada A, Wilson EM, Lubahn DB, et al (1991) Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352: 77–79.
La Spada AR, Roling D, Harding AE, et al (1992) Meiotic stability and genotype-phenotype correlation of the expanded trinucleotide repeat in X-linked spinal and bulbar muscular atrophy. Nature Genet 2: 301–304.
Mhatre AN, Trifiro MA, Kaufman M, et al (1993) Reduced transcriptional regulatory competence of the androgen receptor in X-linked spinal and bulbar muscular atrophy. Nature Genet 5: 184–187.
Orr HT, Chung M, Banfi S, et al (1993) Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nature Genet 4: 221–226.
Perutz MF, Johnson T, Suzuki M, Finch JT (1994) Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc Natl Acad Sci USA 91: 5355–5358.
Salazar-Grueso EF, Kim S, Kim H (1991) Embryonic mouse spinal cord motor neuron hybrid cells. Neuroreport 2: 505–508.
Sobue G, Hashizume Y, Mukai E, et al (1989) X-linked recessive bulbospinal neuronopathy. A clinicopathological study. Brain 112: 209–232.
Warner CL, Griffin JE, Wilson JD, et al (1992) X-linked spinomuscular atrophy: a kindred with associated abnormal receptor binding. Neurology 42: 2181–2184.
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Fischbeck, K.H. Kennedy disease. J Inherit Metab Dis 20, 152–158 (1997). https://doi.org/10.1023/A:1005344403603
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DOI: https://doi.org/10.1023/A:1005344403603