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Proc Natl Acad Sci U S A. 2018 Apr 17;115(16):4234-4239. doi: 10.1073/pnas.1716617115. Epub 2018 Apr 2.

Intron retention induced by microsatellite expansions as a disease biomarker.

Author information

1
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, College of Medicine, University of Florida, Gainesville, FL 32610; ljsznajder@ufl.edu mswanson@ufl.edu.
2
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, College of Medicine, University of Florida, Gainesville, FL 32610.
3
Department of Neurology, University of Rochester, Rochester, NY 14642.
4
McKnight Brain Institute, Department of Neurology and Center for Translational Research in Neurodegenerative Disease, University of Florida, College of Medicine, Gainesville, FL 32610.
5
Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, 61-614 Poznan, Poland.
6
Neurological Institute, Houston Methodist Hospital, Houston, TX 77030.

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:

RNA splicing; amyotrophic lateral sclerosis; intron retention; microsatellite; myotonic dystrophy

PMID:
29610297
PMCID:
PMC5910826
DOI:
10.1073/pnas.1716617115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: M.S.S. is a member of the scientific advisory board of Locana, Inc.

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