Repeat instability: mechanisms of dynamic mutations

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Abstract

Disease-causing repeat instability is an important and unique form of mutation that is linked to more than 40 neurological, neurodegenerative and neuromuscular disorders. DNA repeat expansion mutations are dynamic and ongoing within tissues and across generations. The patterns of inherited and tissue-specific instability are determined by both gene-specific cis-elements and trans-acting DNA metabolic proteins. Repeat instability probably involves the formation of unusual DNA structures during DNA replication, repair and recombination. Experimental advances towards explaining the mechanisms of repeat instability have broadened our understanding of this mutational process. They have revealed surprising ways in which metabolic pathways can drive or protect from repeat instability.

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Most cited references 155

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The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function.

N L Chamberlain, E D Driver, R L Miesfeld (1994)

Some transcription factors contain stretches of polyglutamine encoded by repeats of the trinucleotide CAG. Expansion of the CAG repeat in the androgen receptor (AR) has been correlated with the incidence and severity of X-linked spinal and bulbar muscular atrophy (Kennedy's disease). In order to understand the relationship of this mutation to AR function, we constructed ARs that varied in the position and size of the polyglutamine tract, and assayed for the abilities of these mutant receptors to bind androgen and to activate transcription of several different AR-responsive reporter genes. Elimination of the tract in both human and rat AR resulted in elevated transcriptional activation activity, strongly suggesting that the presence of the polyglutamine tract is inhibitory to transactivation. Progressive expansion of the CAG repeat in human AR caused a linear decrease of transactivation function. Importantly, expansion of the tract did not completely eliminate AR activity. We postulate that this residual AR activity may be sufficient for development of male primary and secondary sex characteristics, but may fall below a threshold level of activity necessary for normal maintenance of motor neuron function. This functional abnormality may be representative of other genetic diseases that are associated with CAG expansion mutations in open reading frames, such as spinocerebellar ataxia type I and Huntington's disease.

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Comparative aspects of the brain growth spurt

John Dobbing, Jean Sands (1979)

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Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis.

Peter J Detloff, Ling Chen, Laura Kennedy … (2003)

Huntington disease is caused by the expansion of a CAG repeat encoding an extended glutamine tract in a protein called huntingtin. Although the mutant protein is widely expressed, the earliest and most striking neuropathological changes are observed in the striatum. Here we show dramatic mutation length increases (gains of up to 1000 CAG repeats) in human striatal cells early in the disease course, most likely before the onset of pathological cell loss. Studies of knock-in HD mouse models indicate that the size of the initial CAG repeat mutation may influence both onset and tissue-specific patterns of age-dependent, expansion-biased mutation length variability. Given that CAG repeat length strongly correlates with clinical severity, we suggest that somatic increases of mutation length may play a major role in the progressive nature and cell-selective aspects of both adult-onset and juvenile-onset HD pathogenesis and we discuss the implications of this interpretation of the data presented.

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Author and article information

Journal

Title: Nature Reviews Genetics

Abbreviated Title: Nat Rev Genet

Publisher: Springer Science and Business Media LLC

ISSN (Print): 1471-0056

ISSN (Electronic): 1471-0064

Publication date Created: October 2005

Publication date (Print): October 2005

Volume: 6

Issue: 10

Pages: 729-742

Article

DOI: 10.1038/nrg1689

PubMed ID: 16205713

SO-VID: bfcb1b13-0d61-4c57-8273-4d28ca6b2e1f

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Repeat instability: mechanisms of dynamic mutations

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The Dynamic Brain

Most cited references 155

The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function.

Comparative aspects of the brain growth spurt

Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis.

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