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.

Mentions: Over the past two decades our thinking about the links between STRs and human diseases has been dominated by neurological disorders known as trinucleotide repeat expansion diseases (TREDs) [8,9]. There are over 20 diseases that belong to this group, the best known of which are fragile X syndrome (FXS), myotonic dystrophy type 1 (DM1), Huntington's disease (HD) and spinocerebellar ataxias (SCAs). FXS is caused by an expanded CGG repeat located in the 5' untranslated region (UTR) of the fragile X mental retardation 1 gene (FMR1); DM1 is triggered by an expanded CUG repeat located in the 3' UTR of the dystrophia myotonica protein kinase gene (DMPK); and HD is caused by an abnormally elongated CAG repeat located in the open reading frame of the Huntingtin gene (HTT), which is translated to form a polyglutamine tract in the protein (Figure 1a-c). The repeat type and localization determines the mechanism of pathogenesis, which can be impaired transcription (FXS, Figure 1a), transcript toxicity (DM1, Figure 1b) or protein toxicity (HD and SCAs; Figure 1c) [10,11].

Kozlowski P, Sobczak K, Krzyzosiak WJ - Genome Med (2010)

Bottom Line: Recently, long TGG repeat tracts were shown to be implicated in a genomic disorder resulting from chromosome 14q32.2 deletion.Various different mechanisms might trigger this deletion, and looking at the problem from a structural biology perspective may help.Deeper insight into repeated sequences and their features may shed light on the mechanisms involved in this microdeletion and similar genomic rearrangements.

Affiliation: Laboratory of Cancer Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland. not@valid.com.

Abstract: Among the various sequence repeats that shape the human genome, trinucleotide repeats have attracted special interest as a result of their involvement in a class of human genetic disorders known as triplet repeat expansion diseases. Recently, long TGG repeat tracts were shown to be implicated in a genomic disorder resulting from chromosome 14q32.2 deletion. Various different mechanisms might trigger this deletion, and looking at the problem from a structural biology perspective may help. Deeper insight into repeated sequences and their features may shed light on the mechanisms involved in this microdeletion and similar genomic rearrangements.