Unstable simple sequence repeat expansions and human disease 2011

Author: D. G. Monckton
Submitted: Monday 5th of September 2011 02:14:49 PM
Submitted by: egf
Educational levels: qc2, qc3


A growing number of human diseases are associated with the expansion of simple sequence repeats within the transcribed region of the gene (1-3). In most cases the expansion is of a trinucleotide repeat, often, CAG or CGG, but some disease are associated with the expansion of tetranucleotide (4), pentanucleotide (5) and other larger repeat units. The disorders associated with unstable DNA include fragile X syndrome (6), Friedreich ataxia (7), Huntington disease (8), myotonic dystrophy and many of the spinocerebellar ataxias. Many of these disorders are characterised by wide symptomatic variability within and between families and unusual inheritance patterns. The arrays are polymorphic in the general population, but of a restricted length, usually less than 35 repeats. Alleles greater than 40 repeats are often associated with symptoms. Larger alleles are associated with more severe symptoms and an earlier age of onset. At most loci the expansions are in the range 40 to 80 repeats, however at some loci the expansion can be over 1,000 repeats. In all of these disorders the expanded alleles are genetically unstable in both the germ line and the soma and mutations are generally biased toward expansion. The expansion biased nature, and sex of parent specificity, of germ line repeat stability accounts for the unusual genetic phenomena associated with many of these disorders, including anticipation (decreasing age of onset in successive generations) (9) and the Sherman paradox in fragile X syndrome (increasing penetrance in successive generations) (10). Somatic expansion may play a role in the tissue specificity and progressive nature of the symptoms (11-16). The precise mechanism that gives rise to repeat expansion is not known, but contrary to initial assumptions, repeat expansion is not associated with cell proliferation (17-19) and actually requires components of the DNA mismatch repair pathway (20-22). Thus, expansion does not appear to be mediated by DNA replication slippage, as widely assumed, but more likely by a process of inappropriate DNA mismatch repair (1, 22). Although aspects of the genetics of these disorders are very similar, the downstream pathology is often very different. Similarly, how repeat expansion leads to the phenotype differs between the disorders from clear loss of function effects, to clear gain of function effects. In particular, many of the disorders are associated with the gain of function of a polyglutamine tract expansion and appear to share many pathogenic features in common, including the formation of intranuclear protein aggregates and transcriptional dysregulation (23). Interestingly, a number of disorders including the myotonic dystrophies type 1 and type 2 (24), and probably SCA8 (25, 26), Huntington disease like 2 (27), fragile X-associated tremor ataxia syndrome (28) and SCA10 (29) appear to be mediated by gain of function of toxic RNAs (30). Loss of function effects may be mediated at the level of DNA methylation induced transcriptional repression, as in fragile X syndrome, or through ‘sticky DNA’ mediated transcriptional inhibition in Friedreich ataxia (31). Insights into the molecular pathways underlying these disorders reveal new targets for drug development and hope for new therapeutic interventions.


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D. G. Monckton. Unstable simple sequence repeat expansions and human disease 2011. EUROGENE portal. September 2011. online: http://eurogene.open.ac.uk/content/unstable-simple-sequence-repeat-expansions-and-human-disease-2011


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