Intron retention induced by microsatellite expansions as a disease biomarker

Łukasz J. Sznajder; James D. Thomas; Ellie M. Carrell; Tammy Reid; Karen N. McFarland; John D. Cleary; Ruan Oliveira; Curtis A. Nutter; Kirti Bhatt; Krzysztof Sobczak; Tetsuo Ashizawa; Charles A. Thornton; Laura P.W. Ranum; Maurice S. Swanson

doi:10.1073/pnas.1716617115

Intron retention induced by microsatellite expansions as a disease biomarker

Łukasz J. Sznajder, James D. Thomas, Ellie M. Carrell, Tammy Reid, Karen N. McFarland, John D. Cleary, Ruan Oliveira, Curtis A. Nutter, Kirti Bhatt, Krzysztof Sobczak, Tetsuo Ashizawa, Charles A. Thornton, Laura P.W. Ranum, Maurice S. Swanson

Research output: Contribution to journal › Article › peer-review

79 Scopus citations

Abstract

Expansions of simple sequence repeats, or microsatellites, have been linked to ∼30 neurological–neuromuscular diseases. While these expansions occur in coding and noncoding regions, microsatellite sequence and repeat length diversity is more prominent in introns with eight different trinucleotide to hexanucleotide repeats, causing hereditary diseases such as myotonic dystrophy type 2 (DM2), Fuchs endothelial corneal dystrophy (FECD), and C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Here, we test the hypothesis that these GC-rich intronic microsatellite expansions selectively trigger host intron retention (IR). Using DM2, FECD, and C9-ALS/FTD as examples, we demonstrate that retention is readily detectable in affected tissues and peripheral blood lymphocytes and conclude that IR screening constitutes a rapid and inexpensive biomarker for intronic repeat expansion disease.

Original language	English (US)
Pages (from-to)	4234-4239
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	115
Issue number	16
DOIs	https://doi.org/10.1073/pnas.1716617115
State	Published - Apr 17 2018

Keywords

Amyotrophic lateral sclerosis
RNA splicing
intron retention
microsatellite
myotonic dystrophy

ASJC Scopus subject areas

General

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10.1073/pnas.1716617115

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Sznajder, Ł. J., Thomas, J. D., Carrell, E. M., Reid, T., McFarland, K. N., Cleary, J. D., Oliveira, R., Nutter, C. A., Bhatt, K., Sobczak, K., Ashizawa, T., Thornton, C. A., Ranum, L. P. W., & Swanson, M. S. (2018). Intron retention induced by microsatellite expansions as a disease biomarker. Proceedings of the National Academy of Sciences of the United States of America, 115(16), 4234-4239. https://doi.org/10.1073/pnas.1716617115

Sznajder, ŁJ, Thomas, JD, Carrell, EM, Reid, T, McFarland, KN, Cleary, JD, Oliveira, R, Nutter, CA, Bhatt, K, Sobczak, K, Ashizawa, T, Thornton, CA, Ranum, LPW & Swanson, MS 2018, 'Intron retention induced by microsatellite expansions as a disease biomarker', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 16, pp. 4234-4239. https://doi.org/10.1073/pnas.1716617115

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title = "Intron retention induced by microsatellite expansions as a disease biomarker",

abstract = "Expansions of simple sequence repeats, or microsatellites, have been linked to ∼30 neurological–neuromuscular diseases. While these expansions occur in coding and noncoding regions, microsatellite sequence and repeat length diversity is more prominent in introns with eight different trinucleotide to hexanucleotide repeats, causing hereditary diseases such as myotonic dystrophy type 2 (DM2), Fuchs endothelial corneal dystrophy (FECD), and C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Here, we test the hypothesis that these GC-rich intronic microsatellite expansions selectively trigger host intron retention (IR). Using DM2, FECD, and C9-ALS/FTD as examples, we demonstrate that retention is readily detectable in affected tissues and peripheral blood lymphocytes and conclude that IR screening constitutes a rapid and inexpensive biomarker for intronic repeat expansion disease.",

keywords = "Amyotrophic lateral sclerosis, RNA splicing, intron retention, microsatellite, myotonic dystrophy",

author = "Sznajder, {{\L}ukasz J.} and Thomas, {James D.} and Carrell, {Ellie M.} and Tammy Reid and McFarland, {Karen N.} and Cleary, {John D.} and Ruan Oliveira and Nutter, {Curtis A.} and Kirti Bhatt and Krzysztof Sobczak and Tetsuo Ashizawa and Thornton, {Charles A.} and Ranum, {Laura P.W.} and Swanson, {Maurice S.}",

note = "Funding Information: ACKNOWLEDGMENTS. We thank participating patients and A. Berglund and E. Wang for comments on the manuscript. This work was supported NIH Grants NS058901 and NS098819 (to M.S.S. and L.P.W.R.), NS040389 (to L.P.W.R.), NS048843 (to C.A.T.), and NS083564 (to T.A.); a Target ALS grant (to L.P.W.R.); and Muscular Dystrophy Association grants (to M.S.S. and L.P.W.R.). During this study, {\L}.J.S. was a postdoctoral fellow of the Myotonic Dystrophy and Wyck Foundations. Publisher Copyright: {\textcopyright} 2018 National Academy of Sciences. All Rights Reserved.",

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doi = "10.1073/pnas.1716617115",

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AU - Sznajder, Łukasz J.

AU - Thomas, James D.

AU - Carrell, Ellie M.

AU - Reid, Tammy

AU - McFarland, Karen N.

AU - Cleary, John D.

AU - Oliveira, Ruan

AU - Nutter, Curtis A.

AU - Bhatt, Kirti

AU - Sobczak, Krzysztof

AU - Ashizawa, Tetsuo

AU - Thornton, Charles A.

AU - Ranum, Laura P.W.

AU - Swanson, Maurice S.

N1 - Funding Information: ACKNOWLEDGMENTS. We thank participating patients and A. Berglund and E. Wang for comments on the manuscript. This work was supported NIH Grants NS058901 and NS098819 (to M.S.S. and L.P.W.R.), NS040389 (to L.P.W.R.), NS048843 (to C.A.T.), and NS083564 (to T.A.); a Target ALS grant (to L.P.W.R.); and Muscular Dystrophy Association grants (to M.S.S. and L.P.W.R.). During this study, Ł.J.S. was a postdoctoral fellow of the Myotonic Dystrophy and Wyck Foundations. Publisher Copyright: © 2018 National Academy of Sciences. All Rights Reserved.

PY - 2018/4/17

Y1 - 2018/4/17

N2 - Expansions of simple sequence repeats, or microsatellites, have been linked to ∼30 neurological–neuromuscular diseases. While these expansions occur in coding and noncoding regions, microsatellite sequence and repeat length diversity is more prominent in introns with eight different trinucleotide to hexanucleotide repeats, causing hereditary diseases such as myotonic dystrophy type 2 (DM2), Fuchs endothelial corneal dystrophy (FECD), and C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Here, we test the hypothesis that these GC-rich intronic microsatellite expansions selectively trigger host intron retention (IR). Using DM2, FECD, and C9-ALS/FTD as examples, we demonstrate that retention is readily detectable in affected tissues and peripheral blood lymphocytes and conclude that IR screening constitutes a rapid and inexpensive biomarker for intronic repeat expansion disease.

AB - Expansions of simple sequence repeats, or microsatellites, have been linked to ∼30 neurological–neuromuscular diseases. While these expansions occur in coding and noncoding regions, microsatellite sequence and repeat length diversity is more prominent in introns with eight different trinucleotide to hexanucleotide repeats, causing hereditary diseases such as myotonic dystrophy type 2 (DM2), Fuchs endothelial corneal dystrophy (FECD), and C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Here, we test the hypothesis that these GC-rich intronic microsatellite expansions selectively trigger host intron retention (IR). Using DM2, FECD, and C9-ALS/FTD as examples, we demonstrate that retention is readily detectable in affected tissues and peripheral blood lymphocytes and conclude that IR screening constitutes a rapid and inexpensive biomarker for intronic repeat expansion disease.

KW - Amyotrophic lateral sclerosis

KW - RNA splicing

KW - intron retention

KW - microsatellite

KW - myotonic dystrophy

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JF - Proceedings of the National Academy of Sciences of the United States of America

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ER -

Intron retention induced by microsatellite expansions as a disease biomarker

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