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Human Molecular Genetics Advance Access originally published online on April 19, 2006
Human Molecular Genetics 2006 15(11):1808-1815; doi:10.1093/hmg/ddl103
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© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited

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

Jamie M. Margolis1,2, Benedikt G. Schoser4,5, Melinda L. Moseley1,2, John W. Day2,3 and Laura P.W. Ranum1,2,*

1Department of Genetics, Cell Biology and Development, 2Institute of Human Genetics and 3Department of Neurology, University of Minnesota, MMC 206, 420 Delaware Street, S.E. Minneapolis, MN 55455, USA, 4Department of Neurology and 5Friedrich-Baur Institute, Ludwig-Maximilians University, Munich, Germany

* To whom corresponding author should be addressed. Tel: +1 6126240901; Fax: +1 6126258488; Email: ranum001{at}umn.edu

Received February 28, 2006; Accepted April 7, 2006

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=5000 CCTGs; range=75–11 000), and similar to DM1, repeats 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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