Figure 1

Triplet-repeat-mediated pathological mechanisms of human diseases. (a-c) Diseases associated with the expansion of triplet repeats (TREDs). (a) Expansion of CGG/CCG repeats over 200 repeats in exon 1 of the FMR1 gene located on chromosome X causes methylation of CpG islands in expanded repeats and flanking DNA, which results in the formation of heterochromatin and inhibition of transcription. Loss of FMR1 expression causes FXS in mutation-carrying males; FXS is thus a recessive disease. (b) Expanded CTG repeats (60 to a few thousand) in the 3' UTR of the DMPK gene are transcribed but not translated. Long CUG repeat hairpins cause a toxic dominant RNA gain-of-function effect mediated by sequestration of nuclear RNA-binding proteins, such as the alternative splicing regulator muscleblind-like 1 (MBNL1). There is clear evidence of an RNA gain-of-function effect in at least five TREDs: DM1, DM2 (expanded CCTG repeats), fragile X-associated tremor ataxia syndrome (FXTAS; expanded CGG repeats), Huntington's disease-like 2 (HDL2) and SCA8 (expanded CTG repeats). (c) The mutated HTT gene with expanded CAG repeats (40 to 100 repeats) in the coding region is transcribed and translated into a toxic protein containing an abnormally long polyglutamine domain. Intracellular aggregation of mutant protein is responsible for the pathogenesis of HD. A similar pathological mechanism is postulated for several dominant disorders known as polyglutamine expansion diseases: seven different spinocerebellar ataxias (SCA1, 2, 3, 6, 7, 8 and 17), dentatorubral-pallidoluysian atrophy (DRPLA) and spinal and bulbar muscular atrophy (SBMA). (d) Diseases caused by long TGG repeat tracts. The dominant UPD(14)mat-like phenotype is caused by the deletion of a 1.11 Mb fragment of chromosome 14q32, which is mediated by two interrupted TGG repeat tracts (red boxes A and B). The deleted fragment contains about a dozen protein and short RNA coding genes, including paternally (green) and maternally (red) imprinted genes. The phenotype results from loss of function of two genes, DLK1 and RTL1, and haplo-insufficiency of the others.