DNA repair in the trinucleotide repeat disorders

Lesley Jones, Henry Houlden, Sarah J Tabrizi; The Lancet Neurology, Volume 16, Issue 1, January 2017, Pages 88-96, ISSN 1474-4422, doi:10.1016/S1474-4422(16)30350-7


Some pathogenic mechanisms are common to multiple diseases. For instance, a repeat that prevents gene expression is seen in fragile X syndrome and Friedreich’s ataxia. Mechanisms related to DNA repair have been implicated as modulators of somatic expansion of the disease-associated repeated sequences in mouse modelsof Huntington’s disease, myotonic dystrophy, fragile X syndrome, and Friedreich’s ataxia.

Where next?: To understand the common genetic architecture of trinucleotide repeat disorders and any further genetic susceptibilities in individual disorders, genetic analysis with increased numbers of variants and sample sizes is needed, followed by sequencing approaches to define the phenotype-modifying variants. The findings must then be translated into cell biology analyses to elucidate the mechanisms through which the genetic variants operate. Genes that have roles in the DNA damage response could underpin a common DNA repeat-based mechanism and provide new therapeutic targets (and hence therapeutics) in multiple trinucleotide repeat disorders.