Trinucleotide Repeats in Neurogenetic Disorders

Paulson, Henry L.; Fischbeck, K. H.

doi:10.1146/annurev.ne.19.030196.000455

Cited by 313 publications

(176 citation statements)

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“…We also demonstrate that this behavior depends on the differences in persistence lengths and is independent of the torsional moduli. This increased hyperflexibility of the TRS coincides with the length of repeats (180 -200 units) that demarcates the premutation from the full mutation range in fragile X and myotonic dystrophy and also coincides with the repeat size that leads to far greater expansions (hundreds of repeats) in offspring (1)(2)(3). This correspondence of the region of hyperflexibility with the premutation to full mutation threshold makes it tempting to speculate that triplet repeat expansion is associated with the supercoiling of DNA.…”

Section: Discussionmentioning

confidence: 77%

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Triplet Repeat Instability and DNA Topology: An Expansion Model Based on Statistical Mechanics

Gellibolian

Bacolla

Wells

1997

Journal of Biological Chemistry

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The variance of writhe, the contribution of writhe to supercoiling, and the free energies of supercoiling were calculated for (CTG⅐CAG) n and (CGG⅐CCG) n triplet repeat sequences (TRS) by statistical mechanics from the bending and torsional moduli previously determined. Expansions of these sequences are inherited by nonmendelian transmission and are linked with several hereditary neuromuscular diseases. The variance of writhe was greater for the TRS than for random B-DNA. For random B-DNA, (CGG) n , and (CTG) n , the contribution of writhe to supercoiling was 70, 78, and 79%, whereas the free energy of supercoiling at a length of 10 kilobase pairs was 1040⅐RT, 760⅐RT, and 685⅐RT, respectively. These data indicate that the TRS are preferential sites for the partitioning of supercoiling. Calculations of the differences in free energy of supercoiling between the TRS and random B-DNA revealed a local minimum at ϳ520 base pairs. Human medical genetic studies have shown that individuals carrying up to 180 -200 copies of TRS (540 -600 base pairs, premutations) in the fragile X or myotonic dystrophy gene loci are usually asymptomatic, whereas large expansions (>200 repeats, full mutations), which lead to disease, are observed in their offspring. Therefore, the length corresponding to the local minimum in free energy of supercoiling correlates with the genetic breakpoint between premutation and full mutation. We propose that (a) TRS instability is mediated by DNA mispairing caused by the accumulation of supercoiling within the repeats, and (b) the expansions that take place at the premutation to full mutation threshold are associated with increased mispairing caused by the optimal partitioning of writhe within the TRS at this length.Several human loci associated with neurodegenerative disorders have been shown to carry a new form of mutation, i.e. the expansion of a DNA triplet repeat sequence (TRS) 1 with composition (CTG⅐CAG) n , (CGG⅐CCG) n , or (GAA⅐TTC) n , referred to as (CTG) n , (CGG) n , and (GAA) n , respectively (reviewed in Refs. 1-4). These diseases fall into two categories (1).The first, which includes spinal and bulbar muscular atrophy, Huntington's disease, spinocerebellar ataxia type 1, dentatorubral-pallidoluysian atrophy, and Machado-Joseph disease, is characterized by small expansions of a (CTG) n repeat from the ϳ10 -40 in the normal population to ϳ40 -120 units in diseased individuals that encode a polyglutamine tract in the corresponding gene products. This mutation may impart a gain of function to the mature polypeptides that is deleterious to neuronal activity (1-3).The second, which includes the myotonic dystrophy (dystrophia myotonica (DM)) and the fragile X and E (FRAXA and FRAXE) genes, is characterized by much larger expansions of either a (CTG) n or (CGG) n repeat, respectively, in the untranslated region of the genes. The mechanisms by which these expansions lead to disease are not fully understood (5, 6). The number of repeats is polymorphic in the normal population and ranges from 6 to 5...

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Section: Discussionmentioning

confidence: 77%

“…the expansion of a DNA triplet repeat sequence (TRS) 1 with composition (CTG⅐CAG) n , (CGG⅐CCG) n , or (GAA⅐TTC) n , referred to as (CTG) n , (CGG) n , and (GAA) n , respectively (reviewed in Refs. 1-4).…”

mentioning

confidence: 99%

Triplet Repeat Instability and DNA Topology: An Expansion Model Based on Statistical Mechanics

Gellibolian

Bacolla

Wells

1997

Journal of Biological Chemistry

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“…La Spada et al (2) found that a trinucleotide repeat, CAG was expanded in the first exon of the AR gene in all SBMA patients. This CAG repeat, which normally encodes a polyglutamine tract of 11-34 amino acids, is expanded to 40-62 amino acids in SBMA patients (3). SBMA is characterized pathologically by degeneration of the anterior horn cells, bulbar neurons, and dorsal root ganglion cells.…”

Section: X-linked Spinal and Bulbar Muscular Atrophymentioning

confidence: 99%

Trinucleotide repeats and neuropsychiatric disorders

Shetty

Christopher

2000

Indian J Clin Biochem

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Expansions of trinucleotide repeats at the level of genomic DNA are increasingly recognized as a cause of a number of neuropsychiatric disorders, Triplet repeat disorders are commonly classified into two groups, those with moderate CAG expansions that result in a polyglutamine stretch in the gene products and those with very long expansions, usually non-CAG, that are not translated. The triplet repeat intergeneration and intra-generational instability, and genetic anticipation characterize disorders. Most of the diseases caused by expanded CAG repeat share common features, which include neurodegeneration, a dominant pattern of inheritance and widespread expression of the gene products with neuronal loss restricted to distinct subset of neurons. Neurodegenerative changes associated of CAG expansion disorders is explained in terms of intra and extra cellular aggregation of mutant gene products, the insoluble nature of the protein(s) being attributed to the presence of polyglutamine stretches, hence their neurotoxic effects. Methods based on poymerase chain reaction have become handy in the diagnosis of these genetic disorders. Progress in transgenic animal models for these disorders will be critical for understanding the progress of these disorders and for testing new therapeutic strategies.

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“…HD is therefore a member of a newly de¢ned class of neurodegenerative diseases characterized by CAG expansions, CAG being the codon for glutamine. Hence CAG diseases are also known as polyglutamine diseases (Paulson & Fischbeck 1996;Perutz 1996;Reddy & Housman 1997). Pathologically, HD is characterized by neurodegeneration of the striatum and the deep layers of cerebral cortex (Vonsattel et al 1985; de la Monte et al 1988).…”

Section: Introductionmentioning

confidence: 99%

Altered neurotransmitter receptor expression in transgenic mouse models of Huntington's disease

Jang-Ho

Frey

Alsdorf

et al. 1999

Phil. Trans. R. Soc. Lond. B

213

129

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Alterations in neurotransmitter receptors are a pathological hallmark of the neurodegeneration seen in Huntington's disease (HD). However, the signi¢cance of these alterations has been uncertain, possibly re£ecting simply the loss of brain cells. It is not known for certain whether the alteration of neurotransmitter receptors occurs before the onset of symptoms in human HD. Recently we developed transgenic mice that contain a portion of a human HD gene and develop a progressive abnormal neurological phenotype. Neurotransmitter receptors that are altered in HD (receptors for glutamate, dopamine, acetylcholine and adenosine) are decreased in the brain of transgenic mice, in some cases before the onset of behavioural or motor symptoms. In transgenic mice, neurotransmitter receptor alterations occur before neuronal death. Further, receptor alterations are selective in that certain receptors, namely N-methyl-D-aspartate and g-aminobutyric acid receptors, are unaltered. Finally, receptor decreases are preceded by selective decreases in the corresponding mRNA species, suggesting the altered transcription of speci¢c genes. These results suggest that (i) receptor decreases precede, and therefore might contribute to, the development of clinical symptoms, and (ii) altered transcription of speci¢c genes might be a key pathological mechanism in HD.

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Trinucleotide Repeats in Neurogenetic Disorders

Cited by 313 publications

References 0 publications

Triplet Repeat Instability and DNA Topology: An Expansion Model Based on Statistical Mechanics

Triplet Repeat Instability and DNA Topology: An Expansion Model Based on Statistical Mechanics

Trinucleotide repeats and neuropsychiatric disorders

Altered neurotransmitter receptor expression in transgenic mouse models of Huntington's disease

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