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Myotonic Dystrophy Type 2

International Conference on the Nondystrophic Myotonias June, 2007. Myotonic Dystrophy Type 2. John W. Day, MD, PhD Paul and Sheila Wellstone Muscular Dystrophy Center Departments of Neurology and Pediatrics, and Institute of Human Genetics University of Minnesota. Laura Ranum

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Myotonic Dystrophy Type 2

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  1. International Conference on theNondystrophic MyotoniasJune, 2007 Myotonic Dystrophy Type 2 John W. Day, MD, PhDPaul and Sheila Wellstone Muscular Dystrophy Center Departments of Neurology and Pediatrics, and Institute of Human Genetics University of Minnesota

  2. Laura Ranum University of Minnesota Joline Dalton Randy Daughters Joanne Dehnbostel Christina Liquori Cameron Naughton Jamie Margolis Kenji Takamura University of Florida Maurice Swanson University of Wurzburg Kenneth Ricker Ludwig-Maximi Univ. Munich Benedikt Schosser Baylor College of Medicine Tom Cooper Support from NIH, MDA, GCRC, MMF Acknowledgements

  3. DM1 Genetics Tapscott, Science 289: 1701; 2000

  4. Myotonic Dystrophy Type 2 - - - SIX5 DMWD DMPK CTG RNA - BP CUG mRNA Accumulation P P

  5. CCTG in Intron 1 of ZNF9 1 2 3 4 5 Liquori, et. al. Science 293:864; 2001 (CCTG)n Northern Blot • Zinc finger protein 9 gene • Unrelated to genes at DM1 locus • Similar repeat motifs in DM1 and DM2 • Repeat transcribed but untranslated Brain Heart Muscle Colon Thymus Spleen Kidney Liver Small Intestine Placenta Lung PBLs

  6. DM2 Molecular Diagnostic Battery

  7. DM2 PCR Repeat Assay

  8. Is DM2 a phenocopy of DM1?

  9. EMG in DM2 Cal=50ms Electrical myotonia 90%

  10. 379 affected members of 133 DM2 families Features common to DM1 and DM2 DM1 DM2 Myotonia + + Iridescent Cataracts + + Weakness + + Cardiac Arrhythmia + + Testicular Failure + + Hyperinsulinemia + + Hypo IgG + + Muscle Histology + + Untranslated Expansion + + RNA Inclusions + + RNA CNS/Developmental Effects + – Day, et. al. Neurology 60:657; 2003

  11. IR-sensitive 10 11 12 IR-insensitive IR-B Sens DM1 DM1 N DM2 DM2 N 10% 41% 68% 18% 26% 74% IR-A Insens Insulin receptor splicing in DM2 Savkur, et. al. AJHG, 74:1309; 2004

  12. Altered Splicing Precedes Pathology Muscle Bx @ 28y/o Ins Rec26% IR-B Muscle Bx @ 36y/o Ins Rec4% IR-B Savkur, et. al. AJHG, 74:1309; 2004

  13. Current Model of DM Pathogenesis Day, et. al., Neuromusc Dis 15:5; 2005

  14. CNS Effects of DM1 and DM2 • Do some DM2 CNS effects mirror those of DM1? • Compare adult-onset DM1 with DM2 • Make comparisons in young adults prior to secondary changes • Make measurements quantitatively to reduce bias and allow comparisons across time and between subjects

  15. CNS Effects of DM1 and DM2 FrontalGray Matter Volume Inferior Frontal White Matter FA FrontalCSF Volume Superior Frontal White Matter FA

  16. CNS Effects of DM1 and DM2 Executive Function – Working Memory Delayed Match to Sample Full Scale IQ

  17. Current Model of DM Pathogenesis Day, et. al., Neuromusc Dis 15:5; 2005

  18. But . . .DM1 and DM2 are not identical • DM2 does not mirror DM1 developmental effects • DM2 is generally “milder” than DM1, but: • DM2 is genetically “more severe” than DM1 • DM2 repeats are larger than DM1 • MBNL binds CCUG as well as CUG

  19. Age at Symptom Onset Age at Weakness Onset Age at Cataract Extraction Age at Blood Draw Might DM1-DM2 differences reflect greater potency of CUG rather than CCUG modulation of MBNL? Does Repeat Size Correlate with Severity? Day, et. al. Neurology 60:657; 2003

  20. Homozygous DM2 expansions without increased clinical severity Schoser, et. al. Brain 127:1868; 2004

  21. Normal Myoblast Heterozygous Myoblast Homozygous Myoblast Homozygous patient >5000 repeats for both alleles Might DM1-DM2 differences reflect changes of ZNF9 levels in DM2? Does the DM2 expansion alter ZNF9 expression? Margolis, et. al. HMG 15:1808; 2006

  22. Large CCTG expansions do not prevent ZNF9 expression Control Myoblast Heterozygous Myoblast Homozygous Myoblast ZNF9 Exon 5 Riboprobe GAPDH Riboprobe Margolis, et. al. HMG 15:1808; 2006

  23. Might DM1-DM2 differences reflect effects of ZNF9 transcripts in ribonuclear inclusions? DM2 inclusions have only CCUG – without other aspects of ZNF9 intron 1 Margolis, et. al. HMG 15:1808; 2006

  24. What could explain DM1-DM2 differences? • Non CUG/CCUG Mechanisms • Six5 dysregulation in DM1 • DMPK up or down regulation in DM1 • Non-CUG elements of DMPK 3’-UTR • Other DM1 locus effects • Disease-specific modifications of CUG/CCUG effects • Different tissue and cell-specific expression patterns of DMPK and ZNF9 • Different temporal expression patterns of DMPK and ZNF9 • Differing CUG and CCUG binding affinities for RNA-BPs

  25. What other diseases involve RNA pathogenesis?

  26. SCA8 - Clinical LOD = 6.8 Θ= 0.00 Normal SCA8

  27. SCA8 CTG/CAG bi-directionally expressed Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8 Melinda L Moseley, Tao Zu, Yoshio Ikeda, Wangcai Gao, Anne K Mosemiller, Randy S Daughters, Gang Chen, Marcy R Weatherspoon1, H Brent Clark, Timothy J Ebner, John W Day, Laura P W RanumNATURE GENETICS VOLUME 38(7):758, JULY 2006

  28. Forms PolyQ mouse and human neuronal intranuclear inclusions Moseley, et. al., Nat Gen 38:758; 2006

  29. Conclusions • RNA expansions cause features common to DM1 and DM2 • Differences between DM1 and DM2 of unknown cause • Possible disease-specific modulation of RNA toxic mechanism • Temporal or cell-specific differences in DMPK v ZNF9 expression • Varied effects of CUG v CCUG expansion • siRNA effects of CUG/CAG transcripts • Possible secondary processes in DM1 or DM2 • No evidence ZNF9 expression is altered • Possible altered expression of other DM1 locus genes • Possible non-CUG effects of DMPK 3’UTR • Value of studying novel human disorders • Important to recognize the different faces of DM

  30. In Memory of Kenneth Ricker

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