Triplet repeat expansion in myotonic dystrophy alters the adjacent chromatin structure.

Abstract

Myotonic dystrophy is caused by an expansion of a CTG triplet repeat sequence in the 3' noncoding region of a protein kinase gene, yet the mechanism by which the triplet repeat expansion causes disease remains unknown. This report demonstrates that a DNase I hypersensitive site is positioned 3' of the triplet repeat in the wild-type allele in both fibroblasts and skeletal muscle cells. In three unrelated individuals with myotonic dystrophy that have large expansions of the triplet repeat, the allele with the triplet repeat expansion exhibited both overall DNase I resistance and inaccessibility of nucleases to the adjacent hypersensitive site. These results indicate that the triplet repeat expansion alters the adjacent chromatin structure, establishing a region of condensed chromatin, and suggests a molecular mechanism for myotonic dystrophy.

RNA metabolism in myotonic dystrophy: patient muscle shows decreased insulin receptor RNA and protein consistent with abnormal insulin resistance.

“…The second hypothesis for disease pathogenesis is that the presence of the expanded repeat in chromatin leads to altered chromatin structure (39) and abnormal nucleosomes binding (40,41). The altered chromatin structure could result in longrange effects on gene transcription, perhaps altering expression of both the DM kinase gene and other neighboring genes.…”

Myotonic Dystrophy Type 1 (DM1): From the Genetics to Molecular Mechanisms

“…b. A second mechanism proposed to explain the pathogenesis of DM1 is based on the effect exerted by CTG expanded repeats on chromatin structure (Otten & Tapscott, 1995), which in turn might lead to partial silencing of neighboring DMWD (Dystrophia myotonica-containing WD repeat motif) and SIX5 (Sine oculis homeobox homolog 5) genes (Alwazzan et al, 1999;Klesert et al, 1997;Sarkar et al, 2000). This hypothesis is supported by the fact that DMWD expression levels are reported as decreased in repeat expansion-bearing patients (Alwazzan et al, 1998;Gennarelli et al, 1999).…”

Myotonic Dystrophy Protein Kinase: Structure, Function and Its Possible Role in the Pathogenesis of Myotonic Dystrophy Type 1

“…The (CTG) n repeat tract is located in a genedense region; in fact the expansion overlaps with the promoter region of the downstream neighboring SIX5 gene. SIX5 expression is needed for eye development in the fruit fly and regulates distal limb muscle development in the mouse (Otten & Tapscott, 1995;Ranum & Day, 2004;Wang et al, 1994). In DM1 an anti-sense DMPK transcript is originated from SIX5 regulatory region.…”