Intron mutations and early transcription termination in Duchenne and Becker muscular dystrophy.

Autor: Waldrop MA; The Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA.; Department of Neurology, The Ohio State University, Columbus, Ohio, USA.; Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA., Moore SA; Department of Pathology, The University of Iowa, Iowa City, Iowa, USA., Mathews KD; Depatment of Pediatrics, The University of Iowa, Iowa City, Iowa, USA., Darbro BW; Depatment of Pediatrics, The University of Iowa, Iowa City, Iowa, USA., Medne L; Department of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Finkel R; Department of Neurology, Nemours Children's Hospital, Orlando, Florida, USA., Connolly AM; Department of Neurology, Washington University, Saint Louis, Missouri, USA., Crawford TO; Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA., Drachman D; Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA., Wein N; The Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA., Habib AA; Department of Neurology, Columbia University, New York, New York, USA., Krzesniak-Swinarska MA; Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA., Zaidman CM; Department of Neurology, Washington University, Saint Louis, Missouri, USA., Collins JJ; Department of Pediatric Neurology, Mercy Hospitals, Springfield, Missouri, USA., Jokela M; Neuromuscular Research Center, Tampere University Hospital and University of Tampere, Tampere, Finland.; Division of Clinical Neurosciences, Turku University Hospital and University of Turku, Turku, Finland., Udd B; Neuromuscular Research Center, Tampere University Hospital and University of Tampere, Tampere, Finland., Day JW; Department of Neurology, University of Minnesota Medical Center, Minneapolis, Minnesota, USA., Ortiz-Guerrero G; Department of Neurology, University of Kansas, Kansas City, Kansas, USA., Statland J; Department of Neurology, University of Kansas, Kansas City, Kansas, USA., Butterfield RJ; Department of Pediatrics, The University of Utah School of Medicine, Salt Lake City, Utah, USA., Dunn DM; Department of Human Genetics, The University of Utah School of Medicine, Salt Lake City, Utah, USA., Weiss RB; Department of Pediatrics, The University of Utah School of Medicine, Salt Lake City, Utah, USA.; Department of Human Genetics, The University of Utah School of Medicine, Salt Lake City, Utah, USA., Flanigan KM; The Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA.; Department of Neurology, The Ohio State University, Columbus, Ohio, USA.; Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.
Jazyk: angličtina
Zdroj: Human mutation [Hum Mutat] 2022 Apr; Vol. 43 (4), pp. 511-528. Date of Electronic Publication: 2022 Mar 07.
DOI: 10.1002/humu.24343
Abstrakt: 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-polymerase chain reaction or high-throughput RNA sequencing 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.
(© 2022 Wiley Periodicals LLC.)
Databáze: MEDLINE
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