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Animal genetics
Oct, 2024;55 (5): 733-743.

Exonisation of an intronic L1 element in the dystrophin gene associated with X-linked muscular dystrophy in a Border Collie dog.

Mario Van Poucke, Liesbet Ledeganck, Ling T Guo, G Diane Shelton, Sofie F M Bhatti, Ine Cornelis, Luc Peelman
Author Information
  1. Mario Van Poucke: Department of Veterinary and Biosciences, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium. ORCID
  2. Liesbet Ledeganck: Department of Small Animals, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium. ORCID
  3. Ling T Guo: Department of Pathology, School of Medicine, University of California San Diego, La Jolla, California, USA. ORCID
  4. G Diane Shelton: Department of Pathology, School of Medicine, University of California San Diego, La Jolla, California, USA. ORCID
  5. Sofie F M Bhatti: Department of Small Animals, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium. ORCID
  6. Ine Cornelis: Department of Small Animals, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium. ORCID
  7. Luc Peelman: Department of Veterinary and Biosciences, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium. ORCID
PMID: 39152696 DOI: 10.1111/age.13470

Abstract

X-linked recessive dystrophinopathies are the most common muscular dystrophies (MDs) in humans and dogs. To date, 20 breed-specific MD-associated variants are described in the canine dystrophin gene (DMD), including one associated with dystrophin-deficient MD in the Border Collie mixed breed. Here, we report the diagnosis and follow-up of mild dystrophin-deficient MD in a 5-month-old male Border Collie, associated with a novel DMD variant. Diagnosis was based on neurological examination and laboratory evaluations including creatine kinase activity, electromyography and muscle biopsies with immunofluorescent staining. Inspection of the Sashimi plots of the RNA-seq data from the affected muscle biopsy led to the discovery of a 162-bp���L1 pseudoexon in DMD intron 63, introducing a frameshift and a premature stop codon (NM_001003343.1: c.9271_9272insN[162] p.(Ala3091fs*21)). Reduced DMD mRNA levels were detected for both the non-pseudoexon (50�� less) and pseudoexon (3�� less) containing transcripts in the affected muscle, compared with the level of the non-pseudoexon containing transcript in a control muscle, resulting in very low dystrophin protein levels and the upregulation of utrophin. Because the variant was only found in the affected dog, not in the healthy mother and grandmother, or in 108 unrelated Border Collies from the Belgian population (46 males and 62 females), it was considered a de novo variant. Although the prognosis for dystrophinopathy is generally regarded as poor, the dog stabilised at the age of 6���months and is still clinically stable at the age of 2���years.

Keywords

DMD biopsy canine dystrophin���deficient MD expression pseudoexon utrophin

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MeSH Term

Male
Animals
Dogs
Exons
Dystrophin
Muscular Dystrophy, Animal
Genetic Diseases, X-Linked
Breeding
Base Sequence
Sequence Alignment
Introns

Chemicals

Dystrophin
Journal Article Case Reports

Word Cloud

Created with Highcharts 10.0.0DMDBordermuscledystrophinassociatedMDCollievariantaffectedpseudoexondogX-linkedmuscularcaninegeneincludingdystrophin-deficientbiopsylevelsnon-pseudoexonlesscontainingutrophinagerecessivedystrophinopathiescommondystrophiesMDshumansdogsdate20breed-specificMD-associatedvariantsdescribedonemixedbreedreportdiagnosisfollow-upmild5-month-oldmalenovelDiagnosisbasedneurologicalexaminationlaboratoryevaluationscreatinekinaseactivityelectromyographybiopsiesimmunofluorescentstainingInspectionSashimiplotsRNA-seqdataleddiscovery162-bp���L1intron63introducingframeshiftprematurestopcodonNM_0010033431:c9271_9272insN[162]pAla3091fs*21ReducedmRNAdetected50��3��transcriptscomparedleveltranscriptcontrolresultinglowproteinupregulationfoundhealthymothergrandmother108unrelatedColliesBelgianpopulation46males62femalesconsidereddenovoAlthoughprognosisdystrophinopathygenerallyregardedpoorstabilised6���monthsstillclinicallystable2���yearsExonisationintronicL1elementdystrophydystrophin���deficientexpression

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