Correction of pseudoexon splicing caused by a novel intronic dysferlin mutation

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Abstract: Objective
Dysferlin is a large transmembrane protein that functions in critical processes of membrane repair and vesicle fusion. Dysferlin‐deficiency due to mutations in the dysferlin gene leads to muscular dystrophy (Miyoshi myopathy (MM), limb girdle muscular dystrophy type 2B (LGMD2B), distal myopathy with anterior tibial onset (DMAT)), typically with early adult onset. At least 416 pathogenic dysferlin mutations are known, but for approximately 17% of patients, one or both of their pathogenic variants remain undefined following standard exon sequencing methods that interrogate exons and nearby flanking intronic regions but not the majority of intronic regions.

Methods
We sequenced RNA from myogenic cells to identify a novel dysferlin pathogenic variant in two affected siblings that previously had only one disease‐causing variant identified. We designed antisense oligonucleotides (AONs) to bypass the effects of this mutation on RNA splicing.

Results
We identified a new pathogenic point mutation deep within dysferlin intron 50i. This intronic variant causes aberrant mRNA splicing and inclusion of an additional pseudoexon (PE, we term PE50.1) within the mature dysferlin mRNA. PE50.1 inclusion alters the protein sequence, causing premature translation termination. We identified this mutation in 23 dysferlinopathy patients (seventeen families), revealing it to be one of the more prevalent dysferlin mutations. We used AON‐mediated exon skipping to correct the aberrant PE50.1 splicing events in vitro, which increased normal mRNA production and significantly restored dysferlin protein expression.

Interpretation
Deep intronic mutations can be a common underlying cause of dysferlinopathy, and importantly, could be treatable with AON‐based exon‐skipping strategies

Location
Deutsche Nationalbibliothek Frankfurt am Main
Extent
Online-Ressource
Language
Englisch
Notes
issn: 2328-9503

Classification
Medizin, Gesundheit

Event
Veröffentlichung
(where)
Freiburg
(who)
Universität
(when)
2019
Creator
Dominov, Janice A.
Uyan, Özgün
McKenna‐Yasek, Diane
Nallamilli, Babi Ramesh Reddy
Kergourlay, Virginie
Bartoli, Marc
Levy, Nicolas
Hudson, Judith
Evangelista, Teresinha
Lochmüller, Hanns
Krahn, Martin
Rufibach, Laura
Hegde, Madhuri
Brown, Robert H.

DOI
10.1002/acn3.738
URN
urn:nbn:de:bsz:25-freidok-1495179
Rights
Der Zugriff auf das Objekt ist unbeschränkt möglich.
Last update
14.08.2025, 10:55 AM CEST

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Associated

  • Dominov, Janice A.
  • Uyan, Özgün
  • McKenna‐Yasek, Diane
  • Nallamilli, Babi Ramesh Reddy
  • Kergourlay, Virginie
  • Bartoli, Marc
  • Levy, Nicolas
  • Hudson, Judith
  • Evangelista, Teresinha
  • Lochmüller, Hanns
  • Krahn, Martin
  • Rufibach, Laura
  • Hegde, Madhuri
  • Brown, Robert H.
  • Universität

Time of origin

  • 2019

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