Expansion of a (CAG)n repeat region in a sporadic case of HD

Bozza, Angela; Malagù, S; Calzolari, Elisa; Novelletto, Andrea; Pavoni, M.; Senno, Laura del

doi:10.1111/j.1600-0404.1995.tb01026.x

Cited by 9 publications

(1 citation statement)

References 7 publications

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“…Answers to these questions are of special relevance to familial brain expansion diseases (Mirkin, 2007;Usdin et al, 2015;Richards, 2016;Polyzos and McMurray, 2017) and their idiopathic relatives (Bozza et al, 1995;Ishikawa et al, 1999;Kim et al, 2007).…”

Section: Questions In Advancementioning

confidence: 99%

A proposed reverse transcription mechanism for (CAG)n and similar expandable repeats that cause neurological and other diseases

Franklin

Steele²,

Lindley

2020

Heliyon

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The mechanism of (CAG)n repeat generation, and related expandable repeat diseases in non-dividing cells, is currently understood in terms of a DNA template-based DNA repair synthesis process involving hairpin stabilized slippage, local error-prone repair via MutSβ (MSH2-MSH3) hairpin protective stabilization, then nascent strand extension by DNA polymerases-β and -δ. We advance a very similar slipped hairpin-stabilized model involving MSH2-MSH3 with two key differences: the copying template may also be the nascent pre-mRNA with the repair pathway being mediated by the Y-family error-prone enzymes DNA polymerase-η and DNA polymerase-κ acting as reverse transcriptases. We argue that both DNA-based and RNA-based mechanisms could well be activated in affected non-dividing brain cells in vivo. Here, we compare the advantages of the RNA/RT-based model proposed by us as an adjunct to previously proposed models. In brief, our model depends upon dysregulated innate and adaptive immunity cascades involving AID/APOBEC and ADAR deaminases that are known to be involved in normal locus-specific immunoglobulin somatic hypermutation, cancer progression and somatic mutations at many off-target non-immunoglobulin sites across the genome: we explain how these processes could also play an active role in repeat expansion diseases at RNA polymerase II-transcribed genes.

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Section: Questions In Advancementioning

confidence: 99%

A proposed reverse transcription mechanism for (CAG)n and similar expandable repeats that cause neurological and other diseases

Franklin

Steele²,

Lindley

2020

Heliyon

View full text Add to dashboard Cite

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Molecular Genetics of Huntington’s Disease

MacDonald

1998

Trinucleotide Diseases and Instability

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The Genetic Defect Causing Huntington’s Disease: Repeated in Other Contexts?

Gusella

Persichetti

MacDonald

1997

Mol Med

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Huntington's disease (HD) is a dominantly inherited, untreatable neurodegenerative disorder involving progressive chorea, psychiatric changes, and intellectual decline (1). The most characteristic feature of HD is its peculiar movement disorder which begins subtly and progresses to exaggerated dance-like motions that consume the entire body. HD occurs equally in both sexes and is found in all races, but most frequently (-1 in 10,000) in people of Western European descent (2). Although symptoms may begin at any age, they are usually first manifested between the ages of 30 and 55 and they progressively worsen until death 12-18 years later. The clinical progression of HD is paralleled by neuronal degeneration in the brain. The hallmark of HD is the loss of medium spiny GABAergic projection neurons in a gradient progressing along posteroanterior, dorsoventral, and mediolateral axes of the caudate nucleus (3). Prior to cell death, signs of neuronal dysfunction are evident in recurved dendritic endings and changes in spine density, shape, and size (4). The disorder eventually destroys the architecture of the caudate nucleus and the adjacent putamen, although extensive cell loss also occurs in other regions of the basal ganglia and in the deep layers of the cerebral cortex (5,6). Overall brain weight may be reduced by 25% or more. Although the proximate cause of the neuronal dysfunction and death is not yet known, it is ultimately due to the presence of a mutant gene

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Expansion of a (CAG)n repeat region in a sporadic case of HD

Cited by 9 publications

References 7 publications

A proposed reverse transcription mechanism for (CAG)n and similar expandable repeats that cause neurological and other diseases

A proposed reverse transcription mechanism for (CAG)n and similar expandable repeats that cause neurological and other diseases

Molecular Genetics of Huntington’s Disease

The Genetic Defect Causing Huntington’s Disease: Repeated in Other Contexts?

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