Dynamic mutations in human genes: A review of trinucleotide repeat diseases

Dynamic mutations in human genes result from unstable trinucleotide repeats embedded within the transcribed region. The changeable nature of these mutations from generation to generation is in contrast to the static inheritance of other single-gene mutational events, e.g. point mutations, deletions, insertions and inversions, typically associated with Mendelian inheritance patterns. Intergenerational instability of dynamic mutations within families has provided an explanation for the genetic anticipation, leading to increasing severity or earlier age of onset in successive generations, associated with certain inherited disorders. While models for genomic instability presume that trinucleotide repeat expansion results from disruption of the DNA replication process, experimental evidence has not yet been obtained in support of this contention. Nevertheless, examples of unstable trinucleotide repeats continue to increase, although not all are associated with a specific phenotype. Five disorders resulting from small-scale expansions of CAG repeats within the protein-coding region are known: spinobulbar muscular atrophy, Huntington’s disease, spinocerebellar ataxia type 1, dentatorubral-pallidoluysian atrophy (DRPLA) and Machado-Joseph disease. A sixth disorder, Haw River syndrome, is allelic to DRPLA. Five folate-sensitive chromosomal fragile sites characterized to date, viz. FRAXA, FRAXE, FRAXF, FRA11B and FRA16A, all have large-scale CGG repeat expansion. Two disorders, fragile X syndrome and FRAXE mental retardation, result from instability of CGG repeats in the 5’ untranslated region ofFMR1 andF M R2 genes respectively. FRA11B lies close to chromosome 1 1q deletion endpoints in many Jacobsen syndrome patients and may be related to the deletion event producing partial aneuploidy for 1lq. Expansion of FRAXF and FRA16A has not been associated with a phenotype. Myotonic dystrophy results from a large-scale CTG expansion in the 3’ untranslated region of the myotonin protein kinase gene while Friedreich’s ataxia has recently been found to have a large-scale GAA repeat in the first intron ofX25. This article reviews the characteristics of trinucleotide repeat disorders and summarizes current understanding of the molecular pathophysiology.