X-linked muscular dystrophy in a Labrador Retriever strain: phenotypic and molecular characterisation
Abstract Background Canine models of Duchenne muscular dystrophy (DMD) are a valuable tool to evaluate potential therapies because they faithfully reproduce the human disease. Several cases of dystrophinopathies have been described in canines, but the Golden Retriever muscular dystrophy (GRMD) model...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-08-01
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| Series: | Skeletal Muscle |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13395-020-00239-0 |
| _version_ | 1819326868594098176 |
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| author | Inès Barthélémy Nadège Calmels Robert B. Weiss Laurent Tiret Adeline Vulin Nicolas Wein Cécile Peccate Carole Drougard Christophe Beroud Nathalie Deburgrave Jean-Laurent Thibaud Catherine Escriou Isabel Punzón Luis Garcia Jean-Claude Kaplan Kevin M. Flanigan France Leturcq Stéphane Blot |
| author_facet | Inès Barthélémy Nadège Calmels Robert B. Weiss Laurent Tiret Adeline Vulin Nicolas Wein Cécile Peccate Carole Drougard Christophe Beroud Nathalie Deburgrave Jean-Laurent Thibaud Catherine Escriou Isabel Punzón Luis Garcia Jean-Claude Kaplan Kevin M. Flanigan France Leturcq Stéphane Blot |
| author_sort | Inès Barthélémy |
| collection | DOAJ |
| description | Abstract Background Canine models of Duchenne muscular dystrophy (DMD) are a valuable tool to evaluate potential therapies because they faithfully reproduce the human disease. Several cases of dystrophinopathies have been described in canines, but the Golden Retriever muscular dystrophy (GRMD) model remains the most used in preclinical studies. Here, we report a new spontaneous dystrophinopathy in a Labrador Retriever strain, named Labrador Retriever muscular dystrophy (LRMD). Methods A colony of LRMD dogs was established from spontaneous cases. Fourteen LRMD dogs were followed-up and compared to the GRMD standard using several functional tests. The disease causing mutation was studied by several molecular techniques and identified using RNA-sequencing. Results The main clinical features of the GRMD disease were found in LRMD dogs; the functional tests provided data roughly overlapping with those measured in GRMD dogs, with similar inter-individual heterogeneity. The LRMD causal mutation was shown to be a 2.2-Mb inversion disrupting the DMD gene within intron 20 and involving the TMEM47 gene. In skeletal muscle, the Dp71 isoform was ectopically expressed, probably as a consequence of the mutation. We found no evidence of polymorphism in either of the two described modifier genes LTBP4 and Jagged1. No differences were found in Pitpna mRNA expression levels that would explain the inter-individual variability. Conclusions This study provides a full comparative description of a new spontaneous canine model of dystrophinopathy, found to be 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. |
| first_indexed | 2024-12-24T13:01:47Z |
| format | Article |
| id | doaj.art-4db5e8aca9c9431692a8b17b3323ddbf |
| institution | Directory Open Access Journal |
| issn | 2044-5040 |
| language | English |
| last_indexed | 2024-12-24T13:01:47Z |
| publishDate | 2020-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Skeletal Muscle |
| spelling | doaj.art-4db5e8aca9c9431692a8b17b3323ddbf2022-12-21T16:54:07ZengBMCSkeletal Muscle2044-50402020-08-0110112210.1186/s13395-020-00239-0X-linked muscular dystrophy in a Labrador Retriever strain: phenotypic and molecular characterisationInès Barthélémy0Nadège Calmels1Robert B. Weiss2Laurent Tiret3Adeline Vulin4Nicolas Wein5Cécile Peccate6Carole Drougard7Christophe Beroud8Nathalie Deburgrave9Jean-Laurent Thibaud10Catherine Escriou11Isabel Punzón12Luis Garcia13Jean-Claude Kaplan14Kevin M. Flanigan15France Leturcq16Stéphane Blot17U955 - IMRB, Team 10 – Biology of the neuromuscular system, Inserm, UPEC, EFS, Ecole nationale vétérinaire d’AlfortLaboratoire de biochimie et génétique moléculaire, hôpital Cochin, AP-HP, université Paris Descartes-Sorbonne Paris CitéDepartment of Human Genetics, The University of Utah School of MedicineU955 - IMRB, Team 10 – Biology of the neuromuscular system, Inserm, UPEC, EFS, Ecole nationale vétérinaire d’AlfortSQY Therapeutics, Université de Versailles Saint-Quentin-en-YvelinesThe Center for Gene Therapy, Nationwide Children’s Hospital, The Ohio State UniversitySQY Therapeutics, Université de Versailles Saint-Quentin-en-YvelinesU955 - IMRB, Team 10 – Biology of the neuromuscular system, Inserm, UPEC, EFS, Ecole nationale vétérinaire d’AlfortAix Marseille Université, INSERM, MMG, Bioinformatics & GeneticsLaboratoire de biochimie et génétique moléculaire, hôpital Cochin, AP-HP, université Paris Descartes-Sorbonne Paris CitéU955 - IMRB, Team 10 – Biology of the neuromuscular system, Inserm, UPEC, EFS, Ecole nationale vétérinaire d’AlfortU955 - IMRB, Team 10 – Biology of the neuromuscular system, Inserm, UPEC, EFS, Ecole nationale vétérinaire d’AlfortU955 - IMRB, Team 10 – Biology of the neuromuscular system, Inserm, UPEC, EFS, Ecole nationale vétérinaire d’AlfortUniversité de Versailles Saint-Quentin-en-Yvelines, U1179 INSERM, UFR des Sciences de la SantéLaboratoire de biochimie et génétique moléculaire, hôpital Cochin, AP-HP, université Paris Descartes-Sorbonne Paris CitéThe Center for Gene Therapy, Nationwide Children’s Hospital, The Ohio State UniversityLaboratoire de biochimie et génétique moléculaire, hôpital Cochin, AP-HP, université Paris Descartes-Sorbonne Paris CitéU955 - IMRB, Team 10 – Biology of the neuromuscular system, Inserm, UPEC, EFS, Ecole nationale vétérinaire d’AlfortAbstract Background Canine models of Duchenne muscular dystrophy (DMD) are a valuable tool to evaluate potential therapies because they faithfully reproduce the human disease. Several cases of dystrophinopathies have been described in canines, but the Golden Retriever muscular dystrophy (GRMD) model remains the most used in preclinical studies. Here, we report a new spontaneous dystrophinopathy in a Labrador Retriever strain, named Labrador Retriever muscular dystrophy (LRMD). Methods A colony of LRMD dogs was established from spontaneous cases. Fourteen LRMD dogs were followed-up and compared to the GRMD standard using several functional tests. The disease causing mutation was studied by several molecular techniques and identified using RNA-sequencing. Results The main clinical features of the GRMD disease were found in LRMD dogs; the functional tests provided data roughly overlapping with those measured in GRMD dogs, with similar inter-individual heterogeneity. The LRMD causal mutation was shown to be a 2.2-Mb inversion disrupting the DMD gene within intron 20 and involving the TMEM47 gene. In skeletal muscle, the Dp71 isoform was ectopically expressed, probably as a consequence of the mutation. We found no evidence of polymorphism in either of the two described modifier genes LTBP4 and Jagged1. No differences were found in Pitpna mRNA expression levels that would explain the inter-individual variability. Conclusions This study provides a full comparative description of a new spontaneous canine model of dystrophinopathy, found to be 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.http://link.springer.com/article/10.1186/s13395-020-00239-0DogCanineNeuromuscular disordersAnimal modelDMDLRMD |
| spellingShingle | Inès Barthélémy Nadège Calmels Robert B. Weiss Laurent Tiret Adeline Vulin Nicolas Wein Cécile Peccate Carole Drougard Christophe Beroud Nathalie Deburgrave Jean-Laurent Thibaud Catherine Escriou Isabel Punzón Luis Garcia Jean-Claude Kaplan Kevin M. Flanigan France Leturcq Stéphane Blot X-linked muscular dystrophy in a Labrador Retriever strain: phenotypic and molecular characterisation Skeletal Muscle Dog Canine Neuromuscular disorders Animal model DMD LRMD |
| title | X-linked muscular dystrophy in a Labrador Retriever strain: phenotypic and molecular characterisation |
| title_full | X-linked muscular dystrophy in a Labrador Retriever strain: phenotypic and molecular characterisation |
| title_fullStr | X-linked muscular dystrophy in a Labrador Retriever strain: phenotypic and molecular characterisation |
| title_full_unstemmed | X-linked muscular dystrophy in a Labrador Retriever strain: phenotypic and molecular characterisation |
| title_short | X-linked muscular dystrophy in a Labrador Retriever strain: phenotypic and molecular characterisation |
| title_sort | x linked muscular dystrophy in a labrador retriever strain phenotypic and molecular characterisation |
| topic | Dog Canine Neuromuscular disorders Animal model DMD LRMD |
| url | http://link.springer.com/article/10.1186/s13395-020-00239-0 |
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