DM1 patients have an extraordinarily long CTG repeat. Patient iPS cells have provided new clues on how these repeats contribute to the disease.

Myotonic dystrophy type 1 (DM1) is a genetic disease that targets muscle and other organ systems. Although the effects of the gene mutation are known, the molecular mechanisms responsible are not. In his latest publication, Associate Professor Hideotoshi Sakurai, who studies muscle diseases at CiRA, uses iPS cells to identify a possible candidate.

DM1 patients suffer from myotonia, muscle atrophy, and a shortened lifespan all because of a single mutation. "An abnormal number CTG repeats in the DMPK gene is the causative mutation of DM1 patient," explained Sakurai. While the normal number of repeats in the gene is in the small dozens at most, DMPK in DM1 patients can have thousands of repeats, and as the number of repeats grows, so too does the severity of the disease.

Why these repeats increase in DM1 patients remains a mystery. Because it is a hereditary disease, Sakurai postulated that the causes emerge early in development.

"We can examine patient cells, but that only tells us about the current condition of the CTG repeats. To understand why the repeats grow, we decided to use iPS cells," he said.

iPS cells were prepared from DM1 patient cells and then differentiated into muscle cells and neurons. Although DM1 affects different cell types differently, unexpectedly, the number of CTG repeats increased with time independent of the cell type (iPS cells, muscle cells and neurons).

Looking for explanations, Sakurai suggested that, "the increase in repeats could be due to changes in the chromatin structure." Indeed, his research group found that the chromatin in muscle cells prepared from patient iPS cells took a closed state, whereas those from healthy donors were in the open state.

"This difference is a new clue on how CTG repeats form in DM1 patients," he concluded, proposing that manipulating the status of the chromatin could offer a therapeutic strategy.

• doi:10.1038/srep42522