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Stéphane Blot
Corresponding Author
ORCiD: https://orcid.org/0000-0002-8982-0317
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Background Canine models of Duchenne muscular dystrophy (DMD) are valuable to evaluate therapies because they faithfully reproduce the human disease. Several cases of dystrophinopathies have been described in canines, but the GRMD (Golden Retriever Muscular Dystrophy) model remains the one used in most preclinical studies.
Methods We report a new spontaneous dystrophinopathy in a Labrador retriever strain, named LRMD (Labrador Retriever Muscular Dystrophy), for which a colony was established. Fourteen LRMD dogs were followed-up and compared to the GRMD standard.
Results The clinical features of the GRMD disease were found in LRMD dogs, and the functional tests provided data roughly overlapping those measured in GRMD dogs, with similar inter-individual heterogeneity. Molecular techniques including RNA-sequencing allowed to map and identify the LRMD causal mutation, consisting in a 2.2-Mb inversion disrupting the DMD gene within its intron 20, and involving TMEM47 gene. In skeletal muscles, the Dp71 isoform was ectopically expressed as a probable consequence of the mutation. We found no evidence of polymorphism in the two LTBP4 and Jagged1 modifier genes that would explain the observed inter-individual variability.
Conclusions This study provides a full comparative description of a new spontaneous canine dystrophinopathy, that we demonstrate is phenotypically equivalent to the GRMD model. We report a novel large DNA mutation within the DMD gene and provide evidence that LRMD is a relevant model to pinpoint additional DMD modifier genes.
Keywords
Dog, canine, Neuromuscular disorders, animal model, DMD, LRMD, Dystrophin, Inversion, Dp71
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CURRENT STATUS: Published
View the published article at Skeletal Muscle.
No community comments so far
Editorial decision: Accept
On 08 Jul, 2020
Review #1 received
Received 05 Jul, 2020
Reviewer #2 agreed
On 01 Jul, 2020
Review #2 received
Received 01 Jul, 2020
Reviewer #1 agreed
On 29 Jun, 2020
Reviewers invited
Invitations sent on 28 Jun, 2020
Editor assigned
On 25 Jun, 2020
Submission checks complete
On 24 Jun, 2020
Editor invited
On 24 Jun, 2020
Version 1
Posted 06 Mar, 2020
No comments provided
Editorial decision: Major revision
On 27 Mar, 2020
Review #1 received
Received 26 Mar, 2020
Review #2 received
Received 16 Mar, 2020
Reviewer #2 agreed
On 05 Mar, 2020
Reviewer #1 agreed
On 04 Mar, 2020
Editor assigned
On 02 Mar, 2020
Reviewers invited
Invitations sent on 02 Mar, 2020
Submission checks complete
On 01 Mar, 2020
Editor invited
On 01 Mar, 2020
First submitted
On 27 Feb, 2020
Metrics
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PDF Downloads: ...
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Subject Areas
Animal Science
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A new preprint design is coming!
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See the published version of this preprint at Skeletal Muscle.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Stéphane Blot
Corresponding Author
ORCiD: https://orcid.org/0000-0002-8982-0317
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Skeletal Muscle.
No community comments so far
Editorial decision: Accept
On 08 Jul, 2020
Review #1 received
Received 05 Jul, 2020
Reviewer #2 agreed
On 01 Jul, 2020
Review #2 received
Received 01 Jul, 2020
Reviewer #1 agreed
On 29 Jun, 2020
Reviewers invited
Invitations sent on 28 Jun, 2020
Editor assigned
On 25 Jun, 2020
Submission checks complete
On 24 Jun, 2020
Editor invited
On 24 Jun, 2020
Version 1
Posted 06 Mar, 2020
No comments provided
Editorial decision: Major revision
On 27 Mar, 2020
Review #1 received
Received 26 Mar, 2020
Review #2 received
Received 16 Mar, 2020
Reviewer #2 agreed
On 05 Mar, 2020
Reviewer #1 agreed
On 04 Mar, 2020
Editor assigned
On 02 Mar, 2020
Reviewers invited
Invitations sent on 02 Mar, 2020
Submission checks complete
On 01 Mar, 2020
Editor invited
On 01 Mar, 2020
First submitted
On 27 Feb, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Animal Science
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Skeletal Muscle.
Background Canine models of Duchenne muscular dystrophy (DMD) are valuable to evaluate therapies because they faithfully reproduce the human disease. Several cases of dystrophinopathies have been described in canines, but the GRMD (Golden Retriever Muscular Dystrophy) model remains the one used in most preclinical studies.
Methods We report a new spontaneous dystrophinopathy in a Labrador retriever strain, named LRMD (Labrador Retriever Muscular Dystrophy), for which a colony was established. Fourteen LRMD dogs were followed-up and compared to the GRMD standard.
Results The clinical features of the GRMD disease were found in LRMD dogs, and the functional tests provided data roughly overlapping those measured in GRMD dogs, with similar inter-individual heterogeneity. Molecular techniques including RNA-sequencing allowed to map and identify the LRMD causal mutation, consisting in a 2.2-Mb inversion disrupting the DMD gene within its intron 20, and involving TMEM47 gene. In skeletal muscles, the Dp71 isoform was ectopically expressed as a probable consequence of the mutation. We found no evidence of polymorphism in the two LTBP4 and Jagged1 modifier genes that would explain the observed inter-individual variability.
Conclusions This study provides a full comparative description of a new spontaneous canine dystrophinopathy, that we demonstrate is phenotypically equivalent to the GRMD model. We report a novel large DNA mutation within the DMD gene and provide evidence that LRMD is a relevant model to pinpoint additional DMD modifier genes.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
This is a list of supplementary files associated with this preprint. Click to download.
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