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A repeated case: Expansions in RNA cause myotonic dystrophy
By Birgit Hofmann-Reinert

Researchers have determined that two types of myotonic dystrophy, the most common forms of muscular dystrophy in adults, can be caused by a genetic mutation on either chromosome 3 or 19. The mutation in myotonic dystrophy type 1 (DM1) was identified in 1992 as an expansion of a repeat in the DMPK gene on chromosome 19. DMPK codes for a protein kinase that is found in skeletal muscle, where it likely plays a regulatory role.

Now, Laura Ranum, of the University of Minnesota, Minneapolis, and colleagues have revealed that a clinically similar, but genetically distinct type of myotonic dystrophy, DM2, is caused by an expansion of repeat sequence on chromosome 3. "Our sequencing data…indicate that the expansion is located in intron 1 of the zinc finger protein 9 (ZNF9) gene," the researchers write in the current issue of Science. ZNF9 is also called the cellular nucleic acid-binding protein gene.

The location of the DM2 expansion was confirmed by accessing GNN's genomic sequence data for the contig overlapping ZNF9: "ZNF9 transcripts are broadly expressed and are most abundant in heart and skeletal muscle…, two tissues prominently affected in DM2," the researchers point out. The findings support the hypothesis that repeat expansions expressed only at the RNA level can cause disease.

Myotonic dystrophy is an inherited disease that results in progressive muscle weakness and can cause eye cataracts, disturbances of heart rhythm, hormonal problems, and muscle stiffness. The disease appears to be more common in people of German descent. The symptoms usually become more severe with each successive generation.

The findings make accurate genetic diagnosis for both types of myotonic dystrophy possible. Efforts can now be devoted to the comparison of common features and differences between DM1 and DM2 to better understand and treat the disease.

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Liquori, C.L. et al. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293, 864-867 (August 3, 2001).
Tapscott, S.J. & Thornton, C.A. Reconstructing myotonic dystrophy. Science 293, 816-817 (August 3, 2001).

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