DOI: 10.1002/ana.23992. Splicing biomarkers of disease severity in myotonic dystrophy

Splicing biomarkers of disease severity in myotonic dystrophy

10.1002/ana.23992

Crossref journal-article

Wiley

Annals of Neurology (311)

Abstract

ObjectiveTo develop RNA splicing biomarkers of disease severity and therapeutic response in myotonic dystrophy type 1 (DM1) and type 2 (DM2).MethodsIn a discovery cohort, we used microarrays to perform global analysis of alternative splicing in DM1 and DM2. The newly identified splicing changes were combined with previous data to create a panel of 50 putative splicing defects. In a validation cohort of 50 DM1 subjects, we measured the strength of ankle dorsiflexion (ADF) and then obtained a needle biopsy of tibialis anterior (TA) to analyze splice events in muscle RNA. The specificity of DM‐associated splicing defects was assessed in disease controls. The CTG expansion size in muscle tissue was determined by Southern blot. The reversibility of splicing defects was assessed in transgenic mice by using antisense oligonucleotides to reduce levels of toxic RNA.ResultsForty‐two splicing defects were confirmed in TA muscle in the validation cohort. Among these, 20 events showed graded changes that correlated with ADF weakness. Five other splice events were strongly affected in DM1 subjects with normal ADF strength. Comparison to disease controls and mouse models indicated that splicing changes were DM‐specific, mainly attributable to MBNL1 sequestration, and reversible in mice by targeted knockdown of toxic RNA. Splicing defects and weakness were not correlated with CTG expansion size in muscle tissue.InterpretationAlternative splicing changes in skeletal muscle may serve as biomarkers of disease severity and therapeutic response in myotonic dystrophy. Ann Neurol 2013;74:862–872

Bibliography

Nakamori, M., Sobczak, K., Puwanant, A., Welle, S., Eichinger, K., Pandya, S., Dekdebrun, J., Heatwole, C. R., McDermott, M. P., Chen, T., Cline, M., Tawil, R., Osborne, R. J., Wheeler, T. M., Swanson, M. S., Moxley, R. T., & Thornton, C. A. (2013). Splicing biomarkers of disease severity in myotonic dystrophy. Annals of Neurology, 74(6), 862â872. Portico.

Authors 17

Masayuki Nakamori (first)
Krzysztof Sobczak (additional)
Araya Puwanant (additional)
Steve Welle (additional)
Katy Eichinger (additional)
Shree Pandya (additional)
Jeannne Dekdebrun (additional)
Chad R. Heatwole (additional)
Michael P. McDermott (additional)
Tian Chen (additional)
Melissa Cline (additional)
Rabi Tawil (additional)
Robert J. Osborne (additional)
Thurman M. Wheeler (additional)
Maurice S. Swanson (additional)
Richard T. Moxley (additional)
Charles A. Thornton (additional)

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Dates

Type	When
Created	12 years ago (Aug. 8, 2013, 11:20 a.m.)
Deposited	1 year, 10 months ago (Oct. 6, 2023, 11:28 a.m.)
Indexed	26 minutes ago (Aug. 30, 2025, 7:22 p.m.)
Issued	11 years, 8 months ago (Dec. 1, 2013)
Published	11 years, 8 months ago (Dec. 1, 2013)
Published Online	11 years, 7 months ago (Jan. 21, 2014)
Published Print	11 years, 8 months ago (Dec. 1, 2013)

Funders 7

NIH National Institute of Neurological Disorders and Stroke 10.13039/100000065 National Institute of Neurological Disorders and Stroke
Region: Americas
gov (National government)
Labels10
1. National Institute of Neurological Disorders & Stroke
2. NIH/National Institute of Neurological Disorders and Stroke
3. NIH National Institute of Neurological Disorders and Stroke
4. Instituto Nacional de Trastornos Neurológicos y Accidentes Cerebrovasculares
5. The National Institute of Neurological Disorders and Stroke
6. National Institute of Neurological Disorders and Blindness
7. National Institute of Neurological and Communicative Disorders and Stroke
8. NINDS
9. NINDB
10. NINCDS
Awards1
1. NS048843
NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards3
1. AR049077
2. AR48143
3. AR055947
NIH
Awards2
1. UL1RR024160-06S4
2. K08NS064293
University of Rochester Clinical and Translational Science Institute/Clinical Research Center
Awards1
1. NIH/NCATS/NCRR, UL1RR024160
Saunders Family Fund, Run America, Muscular Dystrophy Association
Cell Science Research Foundation 10.13039/100007451
Uehara Memorial Foundation 10.13039/100008732
Region: Asia
pri (Trusts, charities, foundations (both public and private))
Labels4
1. The Uehara Memorial Foundation
2. Uehara Memorial Life Science Foundation
3. 上原記念生命科学財団
4. UMF

BibTeX

@article{Nakamori_2013, title={Splicing biomarkers of disease severity in myotonic dystrophy}, volume={74}, ISSN={1531-8249}, url={http://dx.doi.org/10.1002/ana.23992}, DOI={10.1002/ana.23992}, number={6}, journal={Annals of Neurology}, publisher={Wiley}, author={Nakamori, Masayuki and Sobczak, Krzysztof and Puwanant, Araya and Welle, Steve and Eichinger, Katy and Pandya, Shree and Dekdebrun, Jeannne and Heatwole, Chad R. and McDermott, Michael P. and Chen, Tian and Cline, Melissa and Tawil, Rabi and Osborne, Robert J. and Wheeler, Thurman M. and Swanson, Maurice S. and Moxley, Richard T. and Thornton, Charles A.}, year={2013}, month=dec, pages={862–872} }

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