Journal article
Intron Mutations and Early Transcription Termination in Duchenne and Becker muscular dystrophy
Human mutation, Vol.43(4), pp.511-528
02/14/2022
DOI: 10.1002/humu.24343
PMCID: PMC9901284
PMID: 35165973
Abstract
DMD pathogenic variants for Duchenne and Becker muscular dystrophy are detectable with high sensitivity by standard clinical exome analyses of genomic DNA. However, up to 7% of DMD mutations are deep intronic and analysis of muscle-derived RNA is an important diagnostic step for patients who have negative genomic testing but abnormal dystrophin expression in muscle. In this study, muscle biopsies were evaluated from 19 patients with clinical features of a dystrophinopathy, but negative clinical DMD mutation analysis. Reverse transcription PCR (RT-PCR) or high-throughput RNA sequencing (RNA-Seq) methods identified 19 mutations with one of three pathogenic pseudoexon types: deep intronic point mutations, deletions or insertions, and translocations. In association with point mutations creating intronic splice acceptor sites, we observed the first examples of DMD pseudo 3'-terminal exon mutations causing high efficiency transcription termination within introns. This connection between splicing and premature transcription termination is reminiscent of U1 snRNP-mediating telescripting in sustaining RNA polymerase II elongation across large genes, such as DMD. We propose a novel classification of three distinct types of mutations identifiable by muscle RNA analysis, each of which differ in potential treatment approaches. Recognition and appropriate characterization may lead to therapies directed toward full-length dystrophin expression for some patients. This article is protected by copyright. All rights reserved.
Details
- Title: Subtitle
- Intron Mutations and Early Transcription Termination in Duchenne and Becker muscular dystrophy
- Creators
- Megan A Waldrop - Department of Pediatrics, The Ohio State University, Columbus, OH, 43205Steven A Moore - Department of Pathology, The University of Iowa, Iowa City, IA, 52242Katherine D Mathews - Depatment of Pediatrics, The University of Iowa, Iowa City, IA, 52242Benjamin W Darbro - Depatment of Pediatrics, The University of Iowa, Iowa City, IA, 52242Livja Medne - Children's Hospital of Philadelphia, Philadelphia, PA, 19104Richard Finkel - Current affiliation: St. Jude Children's Research Hospital, Memphis, TN, 38105Anne M Connolly - Current Affiliation: The Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, 43205Thomas O Crawford - Johns Hopkins University, Baltimore, MD, 21218Daniel Drachman - Johns Hopkins University, Baltimore, MD, 21218Nicolas Wein - The Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, 43205Ali A Habib - Current affiliation: University of California, Irvine, CA, 92697Monika A Krzesniak-Swinarska - Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131Craig M Zaidman - Department of Neurology, Washington University, Saint Louis, MO, 63110James J Collins - Department of Pediatric Neurology, Mercy Hospitals, Springfield, MO, 65804Manu Jokela - Division of Clinical Neurosciences, Turku University Hospital and University of Turku, Turku, FinlandBjarne Udd - Neuromuscular Research Center, Tampere University Hospital and University of Tampere, Tampere, FinlandJohn W Day - Current affiliation: Department of Neurology, Stanford University Medical Center, Palo Alto, CA, 94304Gloria Ortiz-Guerrero - Department of Neurology, University of Kansas, Kansas City, KSJeff Statland - Department of Neurology, University of Kansas, Kansas City, KSRussell J Butterfield - Department of Pediatrics, The University of Utah School of Medicine, Salt Lake City, UT, 84112Diane M Dunn - Department of Human Genetics, The University of Utah School of Medicine, Salt Lake City, UT, 84112Robert B Weiss - Department of Human Genetics, The University of Utah School of Medicine, Salt Lake City, UT, 84112Kevin M Flanigan - Department of Pediatrics, The Ohio State University, Columbus, OH, 43205
- Resource Type
- Journal article
- Publication Details
- Human mutation, Vol.43(4), pp.511-528
- DOI
- 10.1002/humu.24343
- PMID
- 35165973
- PMCID
- PMC9901284
- NLM abbreviation
- Hum Mutat
- eISSN
- 1098-1004
- Grant note
- DOI: 10.13039/100000065, name: National Institute of Neurological Disorders and Stroke, award: NS043264, NS085238, NS053672
- Language
- English
- Date published
- 02/14/2022
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Medical Genetics and Genomics; Neurology (Pediatrics)
- Record Identifier
- 9984216744202771
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