Low-level dystrophin expression attenuating the dystrophinopathy phenotype

Neuromuscular Disorders : NMD
Megan A WaldropKevin M Flanigan

Abstract

The reading frame rule suggests that Duchenne muscular dystrophy (DMD) results from DMD mutations causing an out-of-frame transcript, whereas the milder Becker muscular dystrophy results from mutations causing an in-frame transcript. However, predicted nonsense mutations may instead result in altered splicing and an in-frame transcript. Here we report a 10-year-old boy with a predicted nonsense mutation in exon 42 who had a 6-minute walk time of 157% of that of age matched DMD controls, characterized as intermediate muscular dystrophy. RNA sequencing analysis from a muscle biopsy revealed only 6.0-9.8% of DMD transcripts were in-frame, excluding exon 42, and immunoblot demonstrated only 3.2% dystrophin protein expression. Another potential genetic modifier noted was homozygosity for the protective IAAM LTBP4 haplotype. This case suggests that very low levels of DMD exon skipping and dystrophin protein expression may result in amelioration of skeletal muscle weakness, a finding relevant to current dystrophin-restoring therapies.

Citations

Aug 28, 2018·Annual Review of Pathology·Nazima ShahnoorMichael W Lawlor
Aug 8, 2019·Physiology·Courtney S YoungMelissa J Spencer
Mar 7, 2020·Neurology·Diane E FrankUNKNOWN SKIP-NMD Study Group
Nov 8, 2020·Annals of Neurology·Yvan de FeraudyHelge Amthor
Aug 11, 2018·Molecular Therapy : the Journal of the American Society of Gene Therapy·Dongsheng Duan
Jun 15, 2021·Journal of Neuromuscular Diseases·Craig M McDonaldUNKNOWN the Italian DMD Telethon Registry Study Group, Leuven NMRC Registry Investigators, CINRG Duchenne Natural History Investigat
Dec 1, 2021·Neuropathology and Applied Neurobiology·Tatyana A VetterKevin M Flanigan

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