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Human Molecular Genetics Advance Access published online on April 19, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl103
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© The Author 2006. Published by Oxford University Press. All rights reserved. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oupjournals.org
Received February 28, 2006
Revised April 7, 2006
Accepted April 7, 2006

Article

DM2 intronic expansions: evidence for CCUG accumulation without flanking sequence or effects on ZNF9 mRNA processing or protein expression

Jamie M. Margolis 1, Benedikt G. Schoser 2, Melinda L. Moseley 1, John W. Day 3, and Laura P.W. Ranum 4 *

1 Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA; Institute of Human Genetics, University of Minnesota, Minneapolis, MN, USA
2 Department of Neurology, Ludwig-Maximilians University, Munich, Germany; Friedrich-Baur Institute, Ludwig-Maximilians University, Munich, Germany
3 Institute of Human Genetics, University of Minnesota, Minneapolis, MN, USA; Department of Neurology, University of Minnesota, Minneapolis, MN, USA
4 Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA; Institute of Human Genetics, University of Minnesota, MMC 206, 420 Delaware St. S.E., Minneapolis, MN 55455, USA

* To whom correspondence should be addressed.
Laura P.W. Ranum, E-mail: ranum001{at}umn.edu


  Abstract

Myotonic dystrophy type 2 (DM2) is caused by a CCTG expansion mutation in intron 1 of the zinc finger protein 9 (ZNF9) gene. The mean expansion size in patients is larger than for DM1 or any previously reported disorder (mean=5,000 CCTGs; range=75-11,000), and similar to DM1, repeat containing ribonuclear inclusions accumulate in affected DM2 tissue. Although an RNA gain of function mechanism involving DM1 CUG or DM2 CCUG expansion transcripts is now well established, still debated are the potential role that flanking sequences within the DMPK 3' UTR may have on disease pathogenesis and whether or not decreased expression of DMPK, ZNF9 or neighboring genes at these loci contribute to disease. To address these questions in DM2, we have examined the nucleic acid content of the ribonuclear inclusions and the effects of these large expansions on ZNF9 expression. Using cell lines either haploid or homozygous for the expansion, as well as skeletal muscle biopsy tissue, we demonstrate that pre-mRNAs containing large CCUG expansions are normally spliced and exported from the nucleus, that the expansions do not decrease ZNF9 expression at the mRNA or protein level, and that the ribonuclear inclusions are enriched for the CCUG expansion, but not intronic flanking sequences. These data suggest that the downstream molecular effects of the DM2 mutation are triggered by the accumulation of CCUG repeat tract alone.


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